Airway mucus hyperconcentration in non–cystic fibrosis bronchiectasis

Rationale: Non–cystic fibrosis bronchiectasis is characterized by airway mucus accumulation and sputum production, but the role of mucus concentration in the pathogenesis of these abnormalities has not been characterized. Objectives: This study was designed to: 1) measure mucus concentration and biophysical properties of bronchiectasis mucus; 2) identify the secreted mucins contained in bronchiectasis mucus; 3) relate mucus properties to airway epithelial mucin RNA/protein expression; and 4) explore relationships between mucus hyperconcentration and disease severity. Methods: Sputum samples were collected from subjects with bronchiectasis, with and without chronic erythromycin administration, and healthy control subjects. Sputum percent solid concentrations, total and individual mucin concentrations, osmotic pressures, rheological properties, and inflammatory mediators were measured. Intracellular mucins were measured in endobronchial biopsies by immunohistochemistry and gene expression. MUC5B (mucin 5B) polymorphisms were identified by quantitative PCR. In a replication bronchiectasis cohort, spontaneously expectorated and hypertonic saline-induced sputa were collected, and mucus/mucin concentrations were measured. Measurements and Main Results: Bronchiectasis sputum exhibited increased percent solids, total and individual (MUC5B and MUC5AC) mucin concentrations, osmotic pressure, and elastic and viscous moduli compared with healthy sputum. Within subjects with bronchiectasis, sputum percent solids correlated inversely with FEV1 and positively with bronchiectasis extent, as measured by high-resolution computed tomography, and inflammatory mediators. No difference was detected in MUC5B rs35705950 SNP allele frequency between bronchiectasis and healthy individuals. Hypertonic saline inhalation acutely reduced non–cystic fibrosis bronchiectasis mucus concentration by 5%. Conclusions: Hyperconcentrated airway mucus is characteristic of subjects with bronchiectasis, likely contributes to disease pathophysiology, and may be a target for pharmacotherapy

Determination of the Form Factors for the Decay B0 --> D*-l+nu_l and of the CKM Matrix Element |Vcb|

We present a combined measurement of the Cabibbo-Kobayashi-Maskawa matrix element $|V_{cb}|$ and of the parameters $\rho^2$, $R_1$, and $R_2$, which fully characterize the form factors of the $B^0 \to D^{*-}\ell^{+}\nu_\ell$ decay in the framework of HQET, based on a sample of about 52,800 $B^0 \to D^{*-}\ell^{+}\nu_\ell$ decays recorded by the BABAR detector. The kinematical information of the fully reconstructed decay is used to extract the following values for the parameters (where the first errors are statistical and the second systematic): $\rho^2 = 1.156 \pm 0.094 \pm 0.028$, $R_1 = 1.329 \pm 0.131 \pm 0.044$, $R_2 = 0.859 \pm 0.077 \pm 0.022$, $\mathcal{F}(1)|V_{cb}| = (35.03 \pm 0.39 \pm 1.15) \times 10^{-3}$. By combining these measurements with the previous BABAR measurements of the form factors which employs a different technique on a partial sample of the data, we improve the statistical accuracy of the measurement, obtaining: $\rho^2 = 1.179 \pm 0.048 \pm 0.028, R_1 = 1.417 \pm 0.061 \pm 0.044, R_2 = 0.836 \pm 0.037 \pm 0.022,$ and $\mathcal{F}(1)|V_{cb}| = (34.68 \pm 0.32 \pm 1.15) \times 10^{-3}.$ Using the lattice calculations for the axial form factor $\mathcal{F}(1)$, we extract $|V_{cb}| =(37.74 \pm 0.35 \pm 1.25 \pm ^{1.23}_{1.44}) \times 10^{-3}$, where the third error is due to the uncertainty in $\mathcal{F}(1)$

Study of the Exclusive Initial-State Radiation Production of the DDˉD \bar D System

A study of exclusive production of the $D \bar D$ system through initial-state r adiation is performed in a search for charmonium states, where $D=D^0$ or $D^+$. The $D^0$ mesons are reconstructed in the $D^0 \to K^- \pi^+$, $D^0 \to K^- \pi^+ \pi^0$, and $D^0 \to K^- \pi^+ \pi^+ \pi^-$ decay modes. The $D^+$ is reconstructed through the $D^+ \to K^- \pi^+ \pi^+$ decay mode. The analysis makes use of an integrated luminosity of 288.5 fb$^{-1}$ collected by the BaBar experiment. The $D \bar D$ mass spectrum shows a clear $\psi(3770)$ signal. Further structures appear in the 3.9 and 4.1 GeV/$c^2$ regions. No evidence is found for Y(4260) decays to $D \bar D$, implying an up per limit \frac{\BR(Y(4260)\to D \bar D)}{\BR(Y(4260)\to J/\psi \pi^+ \pi^-)} < 7.6 (95 % confidence level)

Measurements of Branching Fractions, Polarizations, and Direct CP-Violation Asymmetries in B→ρK∗ and B→f0(980)K∗ Decays

We report searches for B -meson decays to the charmless final states ρ K ∗ and f 0 ( 980 ) K ∗ with a sample of 232 × 10 6 B ¯¯¯ B pairs collected with the BABAR detector at the PEP-II e + e − collider. We measure in units of 10 − 6 the following branching fractions, where the first error quoted is statistical and the second systematic, or upper limits are given at the 90% confidence level : B ( B + → ρ 0 K * + ) < 6.1 , B ( B + → ρ + K * 0 ) = 9.6 ± 1.7 ± 1.5 , B ( B 0 → ρ − K * + ) < 12.0 , B ( B 0 → ρ 0 K * 0 ) = 5.6 ± 0.9 ± 1.3 , B ( B + → f 0 ( 980 ) K * + ) = 5.2 ± 1.2 ± 0.5 , and B ( B 0 → f 0 ( 980 ) K * 0 ) < 4.3 . For the significant modes, we also measure the fraction of longitudinal polarization and the charge asymmetry: f L ( B + → ρ + K * 0 ) = 0.52 ± 0.10 ± 0.04 , f L ( B 0 → ρ 0 K * 0 ) = 0.57 ± 0.09 ± 0.08 , A C P ( B + → ρ + K * 0 ) = − 0.01 ± 0.16 ± 0.02 , A C P ( B 0 → ρ 0 K * 0 ) = 0.09 ± 0.19 ± 0.02 , and A C P ( B + → f 0 ( 980 ) K * + ) = − 0.34 ± 0.21 ± 0.03

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Walking with avatars: Gait-related visual information for following a virtual leader

Dynamic situations, such as interactive sports or walking on a busy street, impose high demands on a person's ability to interact with (others in) its environment (i.e., 'interact-ability'). The current study examined how distance regulation, a fundamental component of these interactions, is mediated by different sources of visual information. Participants were presented with a back and forwards moving virtual leader, which they had to follow by walking back and forwards themselves. We presented the leader in several appearances that differed in the presence of segmental (i.e., relative movements of body segments), cadence-related (i.e., sway and bounce), and global (i.e., optical expansion-compression) information. Results indicated that removing segmental motion information from the virtual leader significantly deteriorated both temporal synchronization and spatial accuracy of the follower to the leader, especially when the movement path of the leader was less regular/predictable. However, no difference was found between cadence-related and global motion information appearances. We argue that regulating distance with others effectively requires a versatile attunement to segmental and global motion information depending on the specific task demands. The results further support the notion that detection of especially segmental information allows for more timely 'anticipatory' tuning to another person's locomotor movements and intentions.FWN – Publicaties zonder aanstelling Universiteit Leide

Modeling and Simulation of Mucus Flow in Human Bronchial Epithelial Cell Cultures – Part I: Idealized Axisymmetric Swirling Flow

A multi-mode nonlinear constitutive model for mucus is constructed directly from micro- and macro-rheology experimental data on cell culture mucus, and a numerical algorithm is developed for the culture geometry and idealized cilia driving conditions. This study investigates the roles that mucus rheology, wall effects, and HBE culture geometry play in the development of flow profiles and the shape of the air-mucus interface. Simulations show that viscoelasticity captures normal stress generation in shear leading to a peak in the air-mucus interface at the middle of the culture and a depression at the walls. Linear and nonlinear viscoelastic regimes can be observed in cultures by varying the hurricane radius and mean rotational velocity. The advection-diffusion of a drug concentration dropped at the surface of the mucus flow is simulated as a function of Peclet number