Exploring multivalent carbohydrate–protein interactions by NMR

Nuclear Magnetic Resonance (NMR) has been widely employed to assess diverse features of glycan–protein molecular recognition events. Different types of qualitative and quantitative information at different degrees of resolution and complexity can be extracted from the proper application of the available NMR-techniques. In fact, affinity, structural, kinetic, conformational, and dynamic characteristics of the binding process are available. Nevertheless, except in particular cases, the affinity of lectin-sugar interactions is weak, mostly at the low mM range. This feature is overcome in biological processes by using multivalency, thus augmenting the strength of the binding. However, the application of NMR methods to monitor multivalent lectin–glycan interactions is intrinsically challenging. It is well known that when large macromolecular complexes are formed, the NMR signals disappear from the NMR spectrum, due to the existence of fast transverse relaxation, related to the large size and exchange features. Indeed, at the heart of the molecular recognition event, the associated free-bound chemical exchange process for both partners takes place in a particular timescale. Thus, these factors have to be considered and overcome. In this review article, we have distinguished, in a subjective manner, the existence of multivalent presentations in the glycan or in the lectin. From the glycan perspective, we have also considered whether multiple epitopes of a given ligand are presented in the same linear chain of a saccharide (i.e., poly-LacNAc oligosaccharides) or decorating different arms of a multiantennae scaffold, either natural (as in multiantennae N-glycans) or synthetic (of dendrimer or polymer nature). From the lectin perspective, the presence of an individual binding site at every monomer of a multimeric lectin may also have key consequences for the binding event at different levels of complexity.We thank generous funding by the European Research Council (RECGLYCANMR, Advanced Grant No. 788143), the Agencia Estatal de Investigación (Spain) for grant PDI2021-1237810B-C21, and CIBERES, an initiative of Instituto de Salud Carlos III (ISCIII), Madrid, Spain. We also thank Marie-Skłodowska-Curie actions (TN BactiVax, under grant agreement No. 860325)

Targeting Galectins With Glycomimetics

Among glycan-binding proteins, galectins, beta-galactoside-binding lectins, exhibit relevant biological roles and are implicated in many diseases, such as cancer and inflammation. Their involvement in crucial pathologies makes them interesting targets for drug discovery. In this review, we gather the last approaches toward the specific design of glycomimetics as potential drugs against galectins. Different approaches, either using specific glycomimetic molecules decorated with key functional groups or employing multivalent presentations of lactose and N-acetyl lactosamine analogs, have provided promising results for binding and modulating different galectins. The review highlights the results obtained with these approximations, from the employment of S-glycosyl compounds to peptidomimetics and multivalent glycopolymers, mostly employed to recognize and/or detecthGal-1 andhGal-3.We thank the European Research Council (RECGLYCANMR, Advanced Grant no. 788143), ISCIII (Grant PRB3 IPT17/0019 to AG), and the Agencia Estatal de Investigacion (Spain) for Grants RTI2018-094751-B-C21, Ramon y Cajal contract to AA and the Severo Ochoa Excellence Accreditation (SEV-2016-0644)

The XMM-LSS survey. Survey design and first results

We have designed a medium deep large area X-ray survey with XMM - the XMM Large Scale Structure survey, XMM-LSS - with the scope of extending the cosmological tests attempted using ROSAT cluster samples to two redshift bins between 0<z<1 while maintaining the precision of earlier studies. Two main goals have constrained the survey design: the evolutionary study of the cluster-cluster correlation function and of the cluster number density. The results are promising and, so far, in accordance with our predictions as to the survey sensitivity and cluster number density. The feasibility of the programme is demonstrated and further X-ray coverage is awaited in order to proceed with a truly significant statistical analysis. (Abridged)Comment: Published in Journal of Cosmology and Astroparticle Physic

TESS discovery of a super-Earth and two sub-Neptunes orbiting the bright, nearby, Sun-like star HD 22946

We report the Transiting Exoplanet Survey Satellite (TESS) discovery of a three-planet system around the bright Sun-like star HD~22946(V=8.3 mag),also known as TIC~100990000, located 63 parsecs away.The system was observed by TESS in Sectors 3, 4, 30 and 31 and two planet candidates, labelled TESS Objects of Interest (TOIs) 411.01 (planet $c$) and 411.02 (planet $b$), were identified on orbits of 9.57 and 4.04 days, respectively. In this work, we validate the two planets and recover an additional single transit-like signal in the light curve, which suggests the presence of a third transiting planet with a longer period of about 46 days.We assess the veracity of the TESS transit signals and use follow-up imaging and time series photometry to rule out false positive scenarios, including unresolved binary systems, nearby eclipsing binaries or background/foreground stars contaminating the light curves. Parallax measurements from Gaia EDR3, together with broad-band photometry and spectroscopic follow-up by TFOP allowed us to constrain the stellar parameters of TOI-411, including its radius of$1.157\pm0.025R_\odot$. Adopting this value, we determined the radii for the three exoplanet candidates and found that planet $b$ is a super-Earth, with a radius of $1.72\pm0.10R_\oplus$, while planet $c$ and $d$ are sub-Neptunian planets, with radii of$2.74\pm0.14R_\oplus$ and $3.23\pm0.19R_\oplus$ respectively. By using dynamical simulations, we assessed the stability of the system and evaluated the possibility of the presence of other undetected, non-transiting planets by investigating its dynamical packing. We find that the system is dynamically stable and potentially unpacked, with enough space to host at least one more planet between $c$ and $d$.(Abridged)Comment: 21 pages, 12 figures. Accepted for publication on A&

The L 98-59 System: Three Transiting, Terrestrial-size Planets Orbiting a Nearby M Dwarf

We report the Transiting Exoplanet Survey Satellite (TESS) discovery of three terrestrial-size planets transiting L 98-59 (TOI-175, TIC 307210830)—a bright M dwarf at a distance of 10.6 pc. Using the Gaia-measured distance and broadband photometry, we find that the host star is an M3 dwarf. Combined with the TESS transits from three sectors, the corresponding stellar parameters yield planet radii ranging from 0.8 R ⊕ to 1.6 R ⊕. All three planets have short orbital periods, ranging from 2.25 to 7.45 days with the outer pair just wide of a 2:1 period resonance. Diagnostic tests produced by the TESS Data Validation Report and the vetting package DAVE rule out common false-positive sources. These analyses, along with dedicated follow-up and the multiplicity of the system, lend confidence that the observed signals are caused by planets transiting L 98-59 and are not associated with other sources in the field. The L 98-59 system is interesting for a number of reasons: the host star is bright (V = 11.7 mag, K = 7.1 mag) and the planets are prime targets for further follow-up observations including precision radial-velocity mass measurements and future transit spectroscopy with the James Webb Space Telescope; the near-resonant configuration makes the system a laboratory to study planetary system dynamical evolution; and three planets of relatively similar size in the same system present an opportunity to study terrestrial planets where other variables (age, metallicity, etc.) can be held constant. L 98-59 will be observed in four more TESS sectors, which will provide a wealth of information on the three currently known planets and have the potential to reveal additional planets in the system

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead