Neutrophil String Formation: Hydrodynamic Thresholding and Cellular Deformation during Cell Collisions

Neutrophils unexpectedly display flow-enhanced adhesion (hydrodynamic thresholding) to L-selectin in rolling or aggregation assays. We report that the primary collision efficiency (ε) of flowing neutrophils with preadhered neutrophils on intercellular adhesion molecule-1 (ICAM-1) or fibrinogen also displayed a maximum of ε ~ 0.4–0.45 at a wall shear rate of 100 s-1, an example of thresholding. Primary collision lifetime with no detectable bonding decreased from 130 to 10 ms as wall shear rate increased from 30 to 300 s-1, whereas collision lifetimes with bonding decreased from 300 to 100 ms over this shear range using preadhered neutrophils on ICAM-1, with similar results for fibrinogen. Antibodies against L-selectin, but not against CD11a, CD11b, or CD18, reduced ε at 100 s-1 by \u3e85%. High resolution imaging detected large scale deformation of the flowing neutrophil during the collision at 100 s-1 with the apparent contact area increasing up to ~40 μm2. We observed the formation of long linear string assemblies of neutrophils downstream of neutrophils preadhered to ICAM-1, but not fibrinogen, with a maximum in string formation at 100 s-1. Secondary capture events to the ICAM-1 or fibrinogen coated surfaces after primary collisions were infrequent and short lived, typically lasting from 500 to 3500 ms. Between 5 and 20% of neutrophil interactions with ICAM-1 substrate converted to firm arrest (\u3e3500 ms) and greatly exceeded that observed for fibrinogen, thus defining the root cause of poor string formation on fibrinogen at all shear rates. Additionally, neutrophils mobilized calcium after incorporation into strings. Static adhesion also caused calcium mobilization, as did the subsequent onset of flow. To our knowledge, this is the first report of 1), hydrodynamic thresholding in neutrophil string formation; 2), string formation on ICAM-1 but not on fibrinogen; 3), large cellular deformation due to collisions at a venous shear rate; and 4), mechanosensing through neutrophil β2-integrin/adhesion. The increased contact area during deformation was likely responsible for the hydrodynamic threshold observed in the primary collision efficiency since no increase in primary collision lifetime was detected as shear forces were increased (for either surface coating)

Transport control by coherent zonal flows in the core/edge transitional regime

3D Braginskii turbulence simulations show that the energy flux in the core/edge transition region of a tokamak is strongly modulated - locally and on average - by radially propagating, nearly coherent sinusoidal or solitary zonal flows. The flows are geodesic acoustic modes (GAM), which are primarily driven by the Stringer-Winsor term. The flow amplitude together with the average anomalous transport sensitively depend on the GAM frequency and on the magnetic curvature acting on the flows, which could be influenced in a real tokamak, e.g., by shaping the plasma cross section. The local modulation of the turbulence by the flows and the excitation of the flows are due to wave-kinetic effects, which have been studied for the first time in a turbulence simulation.Comment: 5 pages, 5 figures, submitted to PR

Effect of Vitamin D on serum markers of bone turnover in SLE in a randomised controlled trial

© 2019 Author(s). Objective Bone health in SLE is adversely affected by vitamin D deficiency, inflammatory cytokines and glucocorticoid use. We hypothesised that vitamin D supplementation would increase markers of bone formation and decrease markers of bone resorption in SLE subjects. Methods We studied 43 vitamin D-deficient SLE subjects who participated in a 12-week randomised controlled trial of 2000-4000 IU/day vitamin D supplementation versus placebo. Subjects had inactive SLE (SLE Disease Activity Index ≤4) and were taking D, N-terminal propeptide of type 1 collagen (P1NP) and C-telopeptide (CTX). We tested the effect of vitamin D versus placebo on change (δ) in P1NP and δCTX in an intention-to-treat analysis. Secondary analyses evaluated whether vitamin D affected bone turnover among subjects achieving vitamin D repletion (≥30 ng/mL) or currently taking glucocorticoids. Results 28 subjects were randomised to vitamin D and 15 to placebo. Mean age was 39 years and 40% were using glucocorticoids at enrolment. Repletion was achieved by 46% in the vitamin D group versus none in the placebo group. Changes in bone turnover markers were not significantly different in the vitamin D group versus placebo group (median δP1NP -0.2 vitamin D group vs -1.1 placebo group (p=0.83); median δCTX +3.5 vitamin D group vs -37.0 placebo group (p=0.50)). The effect of vitamin D did not differ based on achieving vitamin D repletion or baseline glucocorticoid use. Conclusion Vitamin D supplementation did not affect the 12-week change in bone turnover markers among SLE subjects in this trial

Barrier-to-autointegration factor 1 protects against a basal cGAS-STING response

Although the pathogen recognition receptor pathways that activate cell-intrinsic antiviral responses are well delineated, less is known about how the host regulates this response to prevent sustained signaling and possible immune-mediated damage. Using a genome-wide CRISPR-Cas9 screening approach to identify host factors that modulate interferon-stimulated gene (ISG) expression, we identified the DNA binding protein Barrier-to-autointegration factor 1 (Banf1), a previously described inhibitor of retrovirus integration, as a modulator of basal cell-intrinsic immunity. Ablation of Banf1 by gene editing resulted in chromatin activation near host defense genes with associated increased expression of ISGs, includin

Patritumab or Placebo Plus Cetuximab and Platinum-Based Therapy in Squamous Cell Carcinoma of the Head and Neck (SCCHN): a Phase 2 Study

BACKGROUND: P is a fully human monoclonal antibody against human epidermal growth factor receptor 3. P blocks activation by the ligand, heregulin (HRG), inducing receptor internalization. Evidence is growing that HRG presence determines disease progression and survival; in a phase 2 study in non–small-cell lung cancer, P + erlotinib increased progression-free survival (PFS) in high HRG mRNA expression (HRG-high) patients. A phase 1b study in SCCHN demonstrated safety, tolerability and tumor response of P + C + cisplatin or carboplatin and informed the P phase 2 dose. January 2016 (N = 15) response rate = 47%; best responses = 3 complete response (CR), 4 partial response (PR) and 8 stable disease (SD). This phase 2 study (NCT02633800) evaluates first-line P + C + platinum (P arm) vs. PBO + C + platinum (PBO arm) in recurrent and/or metastatic (R/M) SCCHN. The primary objective is to evaluate PFS in the HRG-high population (P vs. PBO arms). METHODS: This is arandomized, controlled, double-blind first-line study in Europe. Patients aged ≥ 18 years with confirmed R/M SCCHN, ECOG performance status ≤ 1 and documented HRG expression (per archived or fresh biopsies) are eligible. The primary efficacy endpoint is PFS. Secondary endpoints include overall survival, overall response rate, pharmacokinetics and safety (including human antihuman antibody incidence). Approximately 105 patients will be stratified 2:1 by HRG status (70 high; 35 low), and then randomized 1:1 to the P or PBO arm. All patients will receive either intravenous P (18mg/kg loading dose [LD]; 9mg/kg maintenance dose [MD] every 3 weeks [q3w]) or PBO, and C (400mg/m2 LD; 250mg/m2 MD weekly) + ≤ 6 cycles of cisplatin (100mg/m2 q3w) or carboplatin (area under the curve of 5). Patients demonstrating CR, PR or SD will be treated with P/PBO + C + ≤ 6 cycles platinum for the study duration (until all patients have died or ≥ 13 months postrandomization of last patient); those benefiting may continue treatment uninterrupted in an open-label extension phase until progressive disease, toxicity or withdrawal. Survival status will be obtained ≥ 13 months after discontinuation. The first patient was dosed December 2015 and enrollment is open. Clinical trial information: NCT0263380

Fine Motor Control Underlies the Association Between Response Inhibition and Drawing Skill in Early Development

Previous research shows that the development of response inhibition and drawing skill are linked. The current research investigated whether this association reflects a more fundamental link between response inhibition and motor control. In Experiment 1, 3- and 4-year-olds (n = 100) were tested on measures of inhibition, fine motor control, and drawing skill. Data revealed an association between inhibition and fine motor control, which was responsible for most of the association observed with drawing skill. Experiment 2 (n = 100) provided evidence that, unlike fine motor control, gross motor control and inhibition were not associated (after controlling for IQ). Alternative explanations for the link between inhibition and fine motor control are outlined, including a consideration of how these cognitive processes may interact during development

Condensation of microturbulence-generated shear flows into global modes

In full flux-surface computer studies of tokamak edge turbulence, a spectrum of shear flows is found to control the turbulence level and not just the conventional (0,0)-mode flows. Flux tube domains too small for the large poloidal scale lengths of the continuous spectrum tend to overestimate the flows, and thus underestimate the transport. It is shown analytically and numerically that under certain conditions dominant (0,0)-mode flows independent of the domain size develop, essentially through Bose-Einstein condensation of the shear flows.Comment: 5 pages, 4 figure