Discovery of a novel conformational equilibrium in urokinase-type plasminogen activator

Although trypsin-like serine proteases have flexible surface-exposed loops and are known to adopt higher and lower activity conformations, structural determinants for the different conformations have remained largely obscure. The trypsin-like serine protease, urokinase-type plasminogen activator (uPA), is central in tissue remodeling processes and also strongly implicated in tumor metastasis. We solved five X-ray crystal structures of murine uPA (muPA) in the absence and presence of allosteric molecules and/or substrate-like molecules. The structure of unbound muPA revealed an unsuspected non-chymotrypsin-like protease conformation in which two β-strands in the core of the protease domain undergoes a major antiparallel-to-parallel conformational transition. We next isolated two anti-muPA nanobodies; an active-site binding nanobody and an allosteric nanobody. Crystal structures of the muPA:nanobody complexes and hydrogen-deuterium exchange mass spectrometry revealed molecular insights about molecular factors controlling the antiparallel-to-parallel equilibrium in muPA. Together with muPA activity assays, the data provide valuable insights into regulatory mechanisms and conformational flexibility of uPA and trypsin-like serine proteases in general

Gestational age at birth and body size from infancy through adolescence: An individual participant data meta-analysis on 253,810 singletons in 16 birth cohort studies

BACKGROUND: Preterm birth is the leading cause of perinatal morbidity and mortality and is associated with adverse developmental and long-term health outcomes, including several cardiometabolic risk factors and outcomes. However, evidence about the association of preterm birth with later body size derives mainly from studies using birth weight as a proxy of prematurity rather than an actual length of gestation. We investigated the association of gestational age (GA) at birth with body size from infancy through adolescence. METHODS AND FINDINGS: We conducted a two-stage individual participant data (IPD) meta-analysis using data from 253,810 mother-child dyads from 16 general population-based cohort studies in Europe (Denmark, Finland, France, Italy, Norway, Portugal, Spain, the Netherlands, United Kingdom), North America (Canada), and Australasia (Australia) to estimate the association of GA with body mass index (BMI) and overweight (including obesity) adjusted for the following maternal characteristics as potential confounders: education, height, prepregnancy BMI, ethnic background, parity, smoking during pregnancy, age at child's birth, gestational diabetes and hypertension, and preeclampsia. Pregnancy and birth cohort studies from the LifeCycle and the EUCAN-Connect projects were invited and were eligible for inclusion if they had information on GA and minimum one measurement of BMI between infancy and adolescence. Using a federated analytical tool (DataSHIELD), we fitted linear and logistic regression models in each cohort separately with a complete-case approach and combined the regression estimates and standard errors through random-effects study-level meta-analysis providing an overall effect estimate at early infancy (>0.0 to 0.5 years), late infancy (>0.5 to 2.0 years), early childhood (>2.0 to 5.0 years), mid-childhood (>5.0 to 9.0 years), late childhood (>9.0 to 14.0 years), and adolescence (>14.0 to 19.0 years). GA was positively associated with BMI in the first decade of life, with the greatest increase in mean BMI z-score during early infancy (0.02, 95% confidence interval (CI): 0.00; 0.05, p < 0.05) per week of increase in GA, while in adolescence, preterm individuals reached similar levels of BMI (0.00, 95% CI: -0.01; 0.01, p 0.9) as term counterparts. The association between GA and overweight revealed a similar pattern of association with an increase in odds ratio (OR) of overweight from late infancy through mid-childhood (OR 1.01 to 1.02) per week increase in GA. By adolescence, however, GA was slightly negatively associated with the risk of overweight (OR 0.98 [95% CI: 0.97; 1.00], p 0.1) per week of increase in GA. Although based on only four cohorts (n = 32,089) that reached the age of adolescence, data suggest that individuals born very preterm may be at increased odds of overweight (OR 1.46 [95% CI: 1.03; 2.08], p < 0.05) compared with term counterparts. Findings were consistent across cohorts and sensitivity analyses despite considerable heterogeneity in cohort characteristics. However, residual confounding may be a limitation in this study, while findings may be less generalisable to settings in low- and middle-income countries. CONCLUSIONS: This study based on data from infancy through adolescence from 16 cohort studies found that GA may be important for body size in infancy, but the strength of association attenuates consistently with age. By adolescence, preterm individuals have on average a similar mean BMI to peers born at term

Hard color-singlet exchange in dijet events in proton-proton collisions at s=\sqrt{s} = 13 TeV

International audienceEvents where the two leading jets are separated by a pseudorapidity interval devoid of particle activity, known as jet-gap-jet events, are studied in proton-proton collisions at $\sqrt{s} =$ 13 TeV. The signature is expected from hard color-singlet exchange. Each of the highest transverse momentum ($p_\mathrm{T}$) jets must have $p_\mathrm{T}^\text{jet}$$\gt$ 40 GeV and pseudorapidity 1.4 $\lt$$|\eta^\text{jet}|$$\lt$ 4.7, with $\eta^\text{jet1} \eta^\text{jet2}$$\lt$ 0, where $\text{jet1}$ and $\text{jet2}$ are the leading and subleading jets in $p_\mathrm{T}$, respectively. The analysis is based on data collected by the CMS and TOTEM experiments during a low luminosity, high-$\beta^*$ run at the CERN LHC in 2015, with an integrated luminosity of 0.66 pb$^{-1}$. Events with a low number of charged particles with $p_\mathrm{T}$$\gt$ 0.2 GeV in the interval $|\eta|$$\lt$ 1 between the jets are observed in excess of calculations that assume only color-exchange. The fraction of events produced via color-singlet exchange, $f_\text{CSE}$, is measured as a function of $p_\mathrm{T}^\text{jet2}$, the pseudorapidity difference between the two leading jets, and the azimuthal angular separation between the two leading jets. The fraction $f_\text{CSE}$ has values of 0.4-1.0%. The results are compared with previous measurements and with predictions from perturbative quantum chromodynamics. In addition, the first study of jet-gap-jet events detected in association with an intact proton using a subsample of events with an integrated luminosity of 0.40 pb$^{-1}$ is presented. The intact protons are detected with the Roman pot detectors of the TOTEM experiment. The $f_\text{CSE}$ in this sample is 2.91 $\pm$ 0.70 (stat) $^{+1.08}_{-1.01}$ (syst) times larger than that for inclusive dijet production in dijets with similar kinematics