Streamwise-travelling viscous waves in channel flows

The unsteady viscous flow induced by streamwise-travelling waves of spanwise wall velocity in an incompressible laminar channel flow is investigated. Wall waves belonging to this category have found important practical applications, such as microfluidic flow manipulation via electro-osmosis and surface acoustic forcing and reduction of wall friction in turbulent wall-bounded flows. An analytical solution composed of the classical streamwise Poiseuille flow and a spanwise velocity profile described by the parabolic cylinder function is found. The solution depends on the bulk Reynolds number R, the scaled streamwise wavelength (Formula presented.), and the scaled wave phase speed U. Numerical solutions are discussed for various combinations of these parameters. The flow is studied by the boundary-layer theory, thereby revealing the dominant physical balances and quantifying the thickness of the near-wall spanwise flow. The Wentzel–Kramers–Brillouin–Jeffreys (WKBJ) theory is also employed to obtain an analytical solution, which is valid across the whole channel. For positive wave speeds which are smaller than or equal to the maximum streamwise velocity, a turning-point behaviour emerges through the WKBJ analysis. Between the wall and the turning point, the wall-normal viscous effects are balanced solely by the convection driven by the wall forcing, while between the turning point and the centreline, the Poiseuille convection balances the wall-normal diffusion. At the turning point, the Poiseuille convection and the convection from the wall forcing cancel each other out, which leads to a constant viscous stress and to the break down of the WKBJ solution. This flow regime is analysed through a WKBJ composite expansion and the Langer method. The Langer solution is simpler and more accurate than the WKBJ composite solution, while the latter quantifies the thickness of the turning-point region. We also discuss how these waves can be generated via surface acoustic forcing and electro-osmosis and propose their use as microfluidic flow mixing devices. For the electro-osmosis case, the Helmholtz–Smoluchowski velocity at the edge of the Debye–Hückel layer, which drives the bulk electrically neutral flow, is obtained by matched asymptotic expansion

Discovery and characterization of a new family of lytic polysaccharide monooxygenases

Lytic polysaccharide monooxygenases (LPMOs) are a recently discovered class of enzymes capable of oxidizing recalcitrant polysaccharides. They are attracting considerable attention owing to their potential use in biomass conversion, notably in the production of biofuels. Previous studies have identified two discrete sequence-based families of these enzymes termed AA9 (formerly GH61) and AA10 (formerly CBM33). Here, we report the discovery of a third family of LPMOs. Using a chitin-degrading exemplar from Aspergillus oryzae, we show that the three-dimensional structure of the enzyme shares some features of the previous two classes of LPMOs, including a copper active center featuring the 'histidine brace' active site, but is distinct in terms of its active site details and its EPR spectroscopy. The newly characterized AA11 family expands the LPMO clan, potentially broadening both the range of potential substrates and the types of reactive copper-oxygen species formed at the active site of LPMOs

Inferring Visuomotor Priors for Sensorimotor Learning

Sensorimotor learning has been shown to depend on both prior expectations and sensory evidence in a way that is consistent with Bayesian integration. Thus, prior beliefs play a key role during the learning process, especially when only ambiguous sensory information is available. Here we develop a novel technique to estimate the covariance structure of the prior over visuomotor transformations – the mapping between actual and visual location of the hand – during a learning task. Subjects performed reaching movements under multiple visuomotor transformations in which they received visual feedback of their hand position only at the end of the movement. After experiencing a particular transformation for one reach, subjects have insufficient information to determine the exact transformation, and so their second reach reflects a combination of their prior over visuomotor transformations and the sensory evidence from the first reach. We developed a Bayesian observer model in order to infer the covariance structure of the subjects' prior, which was found to give high probability to parameter settings consistent with visuomotor rotations. Therefore, although the set of visuomotor transformations experienced had little structure, the subjects had a strong tendency to interpret ambiguous sensory evidence as arising from rotation-like transformations. We then exposed the same subjects to a highly-structured set of visuomotor transformations, designed to be very different from the set of visuomotor rotations. During this exposure the prior was found to have changed significantly to have a covariance structure that no longer favored rotation-like transformations. In summary, we have developed a technique which can estimate the full covariance structure of a prior in a sensorimotor task and have shown that the prior over visuomotor transformations favor a rotation-like structure. Moreover, through experience of a novel task structure, participants can appropriately alter the covariance structure of their prior

A series of Fas receptor agonist antibodies that demonstrate an inverse correlation between affinity and potency

Receptor agonism remains poorly understood at the molecular and mechanistic level. In this study, we identified a fully human anti-Fas antibody that could efficiently trigger apoptosis and therefore function as a potent agonist. Protein engineering and crystallography were used to mechanistically understand the agonistic activity of the antibody. The crystal structure of the complex was determined at 1.9 Å resolution and provided insights into epitope recognition and comparisons with the natural ligand FasL (Fas ligand). When we affinity-matured the agonist antibody, we observed that, surprisingly, the higher-affinity antibodies demonstrated a significant reduction, rather than an increase, in agonist activity at the Fas receptor. We propose and experimentally demonstrate a model to explain this non-intuitive impact of affinity on agonist antibody signalling and explore the implications for the discovery of therapeutic agonists in general

Sentinel Node Identification Rate and Nodal Involvement in the EORTC 10981-22023 AMAROS Trial

Background The randomized EORTC 10981-22023 AMAROS trial investigates whether breast cancer patients with a tumor-positive sentinel node biopsy (SNB) are best treated with an axillary lymph node dissection (ALND) or axillary radiotherapy (ART). The aim of the current substudy was to evaluate the identification rate and the nodal involvement. Methods The first 2,000 patients participating in the AMAROS trial were evaluated. Associations between the identification rate and technical, patient-, and tumor-related factors were evaluated. The outcome of the SNB procedure and potential further nodal involvement was assessed. Results In 65 patients, the sentinel node could not be identified. As a result, the sentinel node identification rate was 97% (1,888 of 1,953). Variables affecting the success rate were age, pathological tumor size, histology, year of accrual, and method of detection. The SNB results of 65% of the patients (n = 1,220) were negative and the patients underwent no further axillary treatment. The SNB results were positive in 34% of the patients (n = 647), including macrometastases (n = 409, 63%), micrometastases (n = 161, 25%), and isolated tumor cells (n = 77, 12%). Further nodal involvement in patients with macrometastases, micrometastases, and isolated tumor cells undergoing an ALND was 41, 18, and 18%, respectively. Conclusions With a 97% detection rate in this prospective international multicenter study, the SNB procedure is highly effective, especially when the combined method is used. Further nodal involvement in patients with micrometastases and isolated tumor cells in the sentinel node was similar—both were 18%

Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles

<div><p>Recent development of benzoxaborole-based chemistry gave rise to a collection of compounds with great potential in targeting diverse infectious diseases, including human African Trypanosomiasis (HAT), a devastating neglected tropical disease. However, further medicinal development is largely restricted by a lack of insight into mechanism of action (MoA) in pathogenic kinetoplastids. We adopted a multidisciplinary approach, combining a high-throughput forward genetic screen with functional group focused chemical biological, structural biology and biochemical analyses, to tackle the complex MoAs of benzoxaboroles in <i>Trypanosoma brucei</i>. We describe an oxidative enzymatic pathway composed of host semicarbazide-sensitive amine oxidase and a trypanosomal aldehyde dehydrogenase TbALDH3. Two sequential reactions through this pathway serve as the key underlying mechanism for activating a series of 4-aminomethylphenoxy-benzoxaboroles as potent trypanocides; the methylamine parental compounds as pro-drugs are transformed first into intermediate aldehyde metabolites, and further into the carboxylate metabolites as effective forms. Moreover, comparative biochemical and crystallographic analyses elucidated the catalytic specificity of TbALDH3 towards the benzaldehyde benzoxaborole metabolites as xenogeneic substrates. Overall, this work proposes a novel drug activation mechanism dependent on both host and parasite metabolism of primary amine containing molecules, which contributes a new perspective to our understanding of the benzoxaborole MoA, and could be further exploited to improve the therapeutic index of antimicrobial compounds.</p></div

Combinatorial Polymer Electrospun Matrices Promote Physiologically-Relevant Cardiomyogenic Stem Cell Differentiation

Myocardial infarction results in extensive cardiomyocyte death which can lead to fatal arrhythmias or congestive heart failure. Delivery of stem cells to repopulate damaged cardiac tissue may be an attractive and innovative solution for repairing the damaged heart. Instructive polymer scaffolds with a wide range of properties have been used extensively to direct the differentiation of stem cells. In this study, we have optimized the chemical and mechanical properties of an electrospun polymer mesh for directed differentiation of embryonic stem cells (ESCs) towards a cardiomyogenic lineage. A combinatorial polymer library was prepared by copolymerizing three distinct subunits at varying molar ratios to tune the physicochemical properties of the resulting polymer: hydrophilic polyethylene glycol (PEG), hydrophobic poly(ε-caprolactone) (PCL), and negatively-charged, carboxylated PCL (CPCL). Murine ESCs were cultured on electrospun polymeric scaffolds and their differentiation to cardiomyocytes was assessed through measurements of viability, intracellular reactive oxygen species (ROS), α-myosin heavy chain expression (α-MHC), and intracellular Ca2+ signaling dynamics. Interestingly, ESCs on the most compliant substrate, 4%PEG-86%PCL-10%CPCL, exhibited the highest α-MHC expression as well as the most mature Ca2+ signaling dynamics. To investigate the role of scaffold modulus in ESC differentiation, the scaffold fiber density was reduced by altering the electrospinning parameters. The reduced modulus was found to enhance α-MHC gene expression, and promote maturation of myocyte Ca2+ handling. These data indicate that ESC-derived cardiomyocyte differentiation and maturation can be promoted by tuning the mechanical and chemical properties of polymer scaffold via copolymerization and electrospinning techniques

The Nature of Knowledge in Composition and Literary Understanding: The Question of Specificity

↵PETER SMAGORINSKY is Assistant Professor, College of Education, University of Oklahoma, 820 Van Vleet Oval, Norman, OK 73019-0. He specializes in classroom literacy.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Circulating microparticles: square the circle

Background: The present review summarizes current knowledge about microparticles (MPs) and provides a systematic overview of last 20 years of research on circulating MPs, with particular focus on their clinical relevance. Results: MPs are a heterogeneous population of cell-derived vesicles, with sizes ranging between 50 and 1000 nm. MPs are capable of transferring peptides, proteins, lipid components, microRNA, mRNA, and DNA from one cell to another without direct cell-to-cell contact. Growing evidence suggests that MPs present in peripheral blood and body fluids contribute to the development and progression of cancer, and are of pathophysiological relevance for autoimmune, inflammatory, infectious, cardiovascular, hematological, and other diseases. MPs have large diagnostic potential as biomarkers; however, due to current technological limitations in purification of MPs and an absence of standardized methods of MP detection, challenges remain in validating the potential of MPs as a non-invasive and early diagnostic platform. Conclusions: Improvements in the effective deciphering of MP molecular signatures will be critical not only for diagnostics, but also for the evaluation of treatment regimens and predicting disease outcomes