Metabolomics reveals biomarkers in human urine and plasma to predict cytochrome P450 2D6 (CYP2D6) activity.

Individualized assessment of cytochrome P450 2D6 (CYP2D6) activity is usually performed through phenotyping following administration of a probe drug to measure the enzyme's activity. To avoid any iatrogenic harm (allergic drug reaction, dosing error) related to the probe drug, the development of non-burdensome tools for real-time phenotyping of CYP2D6 could significantly contribute to precision medicine. This study focuses on the identification of markers of the CYP2D6 enzyme in human biofluids using an LC-high-resolution mass spectrometry-based metabolomic approach. Plasma and urine samples from healthy volunteers were analysed before and after intake of a daily dose of paroxetine 20 mg over 7 days. CYP2D6 genotyping and phenotyping, using single oral dose of dextromethorphan 5 mg, were also performed in all participants. We report four metabolites of solanidine and two unknown compounds as possible novel CYP2D6 markers. Mean relative intensities of these features were significantly reduced during the inhibition session compared with the control session (n = 37). Semi-quantitative analysis showed that the largest decrease (-85%) was observed for the ion m/z 432.3108 normalized to solanidine (m/z 398.3417). Mean relative intensities of these ions were significantly higher in the CYP2D6 normal-ultrarapid metabolizer group (n = 37) compared with the poor metabolizer group (n = 6). Solanidine intensity was more than 15 times higher in CYP2D6-deficient individuals compared with other volunteers. The applied untargeted metabolomic strategy identified potential novel markers capable of semi-quantitatively predicting CYP2D6 activity, a promising discovery for personalized medicine

Peptidomic analysis reveals proteolytic activity of kefir microorganisms on bovine milk proteins

SCOPE: The microorganisms that make up kefir grains are well known for lactose fermentation, but the extent to which they hydrolyze and consume milk proteins remains poorly understood. Peptidomics technologies were used to examine the proteolytic activity of kefir grains on bovine milk proteins. METHODS AND RESULTS: Gel electrophoresis revealed substantial digestion of milk proteins by kefir grains, with mass spectrometric analysis showing the release of 609 protein fragments and alteration of the abundance of >1,500 peptides that derived from 27 milk proteins. Kefir contained 25 peptides identified from the literature as having biological activity, including those with antihypertensive, antimicrobial, immunomodulatory, opioid and anti-oxidative functions. 16S rRNA and shotgun metagenomic sequencing identified the principle taxa in the culture as Lactobacillus species. CONCLUSION: The model kefir sample contained thousands of protein fragments released in part by kefir microorganisms and in part by native milk proteases

Effectiveness of the combination elvitegravir/cobicistat/tenofovir/emtricitabine (EVG/COB/TFV/FTC) plus darunavir among treatment-experienced patients in clinical practice : A multicentre cohort study

Background: The aim of this study was to investigate the effectiveness and tolerability of the combination elvitegravir/cobicistat/tenofovir/emtricitabine plus darunavir (EVG/COB/TFV/FTC + DRV) in treatment-experienced patients from the cohort of the Spanish HIV/AIDS Research Network (CoRIS). Methods: Treatment-experienced patients starting treatment with EVG/COB/TFV/FTC + DRV during the years 2014-2018 and with more than 24 weeks of follow-up were included. TFV could be administered either as tenofovir disoproxil fumarate or tenofovir alafenamide. We evaluated virological response, defined as viral load (VL) < 50 copies/ml and < 200 copies/ml at 24 and 48 weeks after starting this regimen, stratified by baseline VL (< 50 or ≥ 50 copies/ml at the start of the regimen). Results: We included 39 patients (12.8% women). At baseline, 10 (25.6%) patients had VL < 50 copies/ml and 29 (74.4%) had ≥ 50 copies/ml. Among patients with baseline VL < 50 copies/ml, 85.7% and 80.0% had VL < 50 copies/ml at 24 and 48 weeks, respectively, and 100% had VL < 200 copies/ml at 24 and 48 weeks. Among patients with baseline VL ≥ 50 copies/ml, 42.3% and 40.9% had VL < 50 copies/ml and 69.2% and 68.2% had VL < 200 copies/ml at 24 and 48 weeks. During the first 48 weeks, no patients changed their treatment due to toxicity, and 4 patients (all with baseline VL ≥ 50 copies/ml) changed due to virological failure. Conclusions: EVG/COB/TFV/FTC + DRV was well tolerated and effective in treatment-experienced patients with undetectable viral load as a simplification strategy, allowing once-daily, two-pill regimen with three antiretroviral drug classes. Effectiveness was low in patients with detectable viral loads

All-sky search in early O3 LIGO data for continuous gravitational-wave signals from unknown neutron stars in binary systems

International audienceRapidly spinning neutron stars are promising sources of continuous gravitational waves. Detecting such a signal would allow probing of the physical properties of matter under extreme conditions. A significant fraction of the known pulsar population belongs to binary systems. Searching for unknown neutron stars in binary systems requires specialized algorithms to address unknown orbital frequency modulations. We present a search for continuous gravitational waves emitted by neutron stars in binary systems in early data from the third observing run of the Advanced LIGO and Advanced Virgo detectors using the semicoherent, GPU-accelerated, binaryskyhough pipeline. The search analyzes the most sensitive frequency band of the LIGO detectors, 50–300 Hz. Binary orbital parameters are split into four regions, comprising orbital periods of three to 45 days and projected semimajor axes of two to 40 light seconds. No detections are reported. We estimate the sensitivity of the search using simulated continuous wave signals, achieving the most sensitive results to date across the analyzed parameter space

Search for Lensing Signatures in the Gravitational-Wave Observations from the First Half of LIGO–Virgo’s Third Observing Run

International audienceWe search for signatures of gravitational lensing in the gravitational-wave signals from compact binary coalescences detected by Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) and Advanced Virgo during O3a, the first half of their third observing run. We study: (1) the expected rate of lensing at current detector sensitivity and the implications of a non-observation of strong lensing or a stochastic gravitational-wave background on the merger-rate density at high redshift; (2) how the interpretation of individual high-mass events would change if they were found to be lensed; (3) the possibility of multiple images due to strong lensing by galaxies or galaxy clusters; and (4) possible wave-optics effects due to point-mass microlenses. Several pairs of signals in the multiple-image analysis show similar parameters and, in this sense, are nominally consistent with the strong lensing hypothesis. However, taking into account population priors, selection effects, and the prior odds against lensing, these events do not provide sufficient evidence for lensing. Overall, we find no compelling evidence for lensing in the observed gravitational-wave signals from any of these analyses

Searches for continuous gravitational waves from young supernova remnants in the early third observing run of Advanced LIGO and Virgo

We present results of three wide-band directed searches for continuous gravitational waves from 15 young supernova remnants in the first half of the third Advanced LIGO and Virgo observing run. We use three search pipelines with distinct signal models and methods of identifying noise artifacts. Without ephemerides of these sources, the searches are conducted over a frequency band spanning from 10~Hz to 2~kHz. We find no evidence of continuous gravitational radiation from these sources. We set upper limits on the intrinsic signal strain at 95% confidence level in sample sub-bands, estimate the sensitivity in the full band, and derive the corresponding constraints on the fiducial neutron star ellipticity and $r$-mode amplitude. The best 95% confidence constraints placed on the signal strain are $7.7\times 10^{-26}$ and $7.8\times 10^{-26}$ near 200~Hz for the supernova remnants G39.2--0.3 and G65.7+1.2, respectively. The most stringent constraints on the ellipticity and $r$-mode amplitude reach $\lesssim 10^{-7}$ and $\lesssim 10^{-5}$, respectively, at frequencies above $\sim 400$~Hz for the closest supernova remnant G266.2--1.2/Vela Jr