Three-dimensional viscous rotor flow calculations using a viscous-inviscid interaction approach

A three-dimensional viscous-inviscid interaction analysis was developed to predict the performance of rotors in hover and in forward flight at subsonic and transonic tip speeds. The analysis solves the full-potential and boundary-layer equations by finite-difference numerical procedures. Calculations were made for several different model rotor configurations. The results were compared with predictions from a two-dimensional integral method and with experimental data. The comparisons show good agreement between predictions and test data

Lattice-Boltzmann coupled models for advection-diffusion flow on a wide range of Péclet numbers

YesTraditional Lattice-Boltzmann modelling of advection–diffusion flow is affected by numerical instability if the advective term becomes dominant over the diffusive (i.e., high-Péclet flow). To overcome the problem, two 3D one-way coupled models are proposed. In a traditional model, a Lattice-Boltzmann Navier–Stokes solver is coupled to a Lattice-Boltzmann advection–diffusion model. In a novel model, the Lattice-Boltzmann Navier–Stokes solver is coupled to an explicit finite-difference algorithm for advection–diffusion. The finite-difference algorithm also includes a novel approach to mitigate the numerical diffusivity connected with the upwind differentiation scheme

Characterisation and Performance of three Kenaf coagulation products under different operating conditions

YesThe Sustainable Development Goal (SDG) 6.1, established by the United Nations General Assembly in 2015, targets universal and equitable access to safe and affordable drinking water for all by 2030. An essential factor in achieving this goal is the harnessing of “green” coagulants – naturally occurring, environmentally friendly materials which are effective coagulants for use in water treatment, with good availability in developing countries, inherent renewable properties and ease of biodegradation. In order to gain from these benefits, it is essential to fully understand how such coagulants may best be utilised, particularly concerning their practical application in developing countries. In this study, three different plant-based coagulation products (PCPs), namely Hexane (HxKP), saline (StKP) and crude (CrKP) extracts of Kenaf plant seed (Hibiscus cannabinus, a species of the Hibiscus plant), were applied to high (HTW), medium (MTW) and low (LTW) turbidity water in order to determine their performance and coagulation ability. The ability of the three Kenaf coagulant products (KCPs) to remove hydrophobic fractions of natural organic matter (NOM) was measured. The impact of KCPs on the treated water organic matter content (a known disinfection by-product (DBP) precursor) was examined using known surrogates of natural organic matter (NOM) i.e. the dissolved organic carbon (DOC), ultraviolet absorbance at 254 (UV254) and specific ultraviolet absorbance (SUVA254). Results obtained quantify the implications of using these coagulants during the water disinfection process. A parametric study, measuring the effect of different operating parameters, such as untreated water turbidity, pH, dosages, retention time, and KCP storage time, was completed. Turbidity removal performance for HxKP and StKP was very good with > 90% removal recorded for HTW and MTW, respectively, at pH seven within 2 hours retention time. Images obtained from scanning electron microscopy (SEM) analysis revealed a high likelihood of the coagulation mechanism of KCPs to be adsorption-interparticle bridging brought about by their flake-like structures and surfaces charges. Varying pH had no measurable influence on the coagulation performance of the KCPs. Comparing their efficiency with Moringa Oleifera (MO, a previously researched PCP) and alum showed that HxKP had a negligibly different particle removal as MO. StKP turbidity removal performance was below HxKP by 1% for HTW and LTW and 2% for MTW but performed higher than the CrKP by 5% and 7% in HTW and MTW, respectively. The optimum dosage of HxKP and StKP reduced DBP surrogate values, indicating that its precursor is also minimized, although a slight shift from this optimum dosage showed a significant rise in their concentration thus signifying a potential increase in DBPs during disinfection

Clonotypically similar hybrid ab T cell receptors can exhibit markedly different surface expression, antigen specificity and cross-reactivity

Emerging data indicate that particular major histocompatibility complex (MHC)-bound antigenic peptides can be recognized by identical or nearidentical ab T cell receptors (TCRs) in different individuals. To establish the functional relevance of this phenomenon, we artificially paired a and b chains from closely related TCRs specific for the human leucocyte antigen (HLA)-B*35:01-restricted HIV-1 negative regulatory factor (Nef)- derived epitope VY8 (VPLRPMTY, residues 74–81). Several hybrid TCRs generated in this manner failed to express at the cell surface, despite near homology with naturally isolated ab chain combinations. Moreover, a substantial proportion of those ab TCRs that did express lost specificity for the index VY8 peptide sequence. One such hybrid ab pair gained neo-variant specificity in the context of the VY8 backbone. Collectively, these data show that clonotypically similar TCRs can display profound differences in surface expression, antigen specificity and cross-reactivity with potential relevance for the control of mutable viruses

Illusory perceptions of space and time preserve cross-saccadic perceptual continuity

When voluntary saccadic eye movements are made to a silently ticking clock, observers sometimes think that the second hand takes longer than normal to move to its next position. For a short period, the clock appears to have stopped (chronostasis). Here we show that the illusion occurs because the brain extends the percept of the saccadic target backwards in time to just before the onset of the saccade. This occurs every time we move the eyes but it is only perceived when an external time reference alerts us to the phenomenon. The illusion does not seem to depend on the shift of spatial attention that accompanies the saccade. However, if the target is moved unpredictably during the saccade, breaking perception of the target's spatial continuity, then the illusion disappears. We suggest that temporal extension of the target's percept is one of the mechanisms that 'fill in' the perceptual 'gap' during saccadic suppression. The effect is critically linked to perceptual mechanisms that identify a target's spatial stability

Mutational and Structural Analysis of KIR3DL1 Reveals a Lineage-Defining Allotypic Dimorphism That Impacts Both HLA and Peptide Sensitivity

Killer Ig-like receptors (KIRs) control the activation of human NK cells via interactions with peptide-laden HLAs. KIR3DL1 is a highly polymorphic inhibitory receptor that recognizes a diverse array of HLA molecules expressing the Bw4 epitope, a group with multiple polymorphisms incorporating variants within the Bw4 motif. Genetic studies suggest that KIR3DL1 variation has functional significance in several disease states, including HIV infection. However, owing to differences across KIR3DL1 allotypes, HLA-Bw4, and associated peptides, the mechanistic link with biological outcome remains unclear. In this study, we elucidated the impact of KIR3DL1 polymorphism on peptide-laden HLA recognition. Mutational analysis revealed that KIR residues involved in water-mediated contacts with the HLA-presented peptide influence peptide binding specificity. In particular, residue 282 (glutamate) in the D2 domain underpins the lack of tolerance of negatively charged C-terminal peptide residues. Allotypic KIR3DL1 variants, defined by neighboring residue 283, displayed differential sensitivities to HLA-bound peptide, including the variable HLA-B*57:01-restricted HIV-1 Gag-derived epitope TW10. Residue 283, which has undergone positive selection during the evolution of human KIRs, also played a central role in Bw4 subtype recognition by KIR3DL1. Collectively, our findings uncover a common molecular regulator that controls HLA and peptide discrimination without participating directly in peptide-laden HLA interactions. Furthermore, they provide insight into the mechanics of interaction and generate simple, easily assessed criteria for the definition of KIR3DL1 functional groupings that will be relevant in many clinical applications, including bone marrow transplantation

Dual molecular mechanisms govern escape at immunodominant HLA A2-restricted HIV epitope

Serial accumulation of mutations to fixation in the SLYNTVATL (SL9) immunodominant, HIV p17 Gag-derived, HLA A2-restricted CTL epitope produce the SLFNTIAVL triple mutant ‘ultimate’ escape variant. These mutations in solvent-exposed residues are believed to interfere with TCR recognition, although confirmation has awaited structural verification. Here, we solved a TCR co-complex structure with SL9 and the triple escape mutant to determine the mechanism of immune escape in this eminent system. We show that, in contrast to prevailing hypotheses, the main TCR contact residue is 4N and the dominant mechanism of escape is not via lack of TCR engagement. Instead, mutation of solvent exposed residues in the peptide destabilize the peptide-HLA and reduce peptide density at the cell surface. These results highlight the extraordinary lengths that HIV employs to evade detection by high-affinity TCRs with a broad peptide-binding footprint and necessitate reevaluation of this exemplar model of HIV TCR escape

Expressions 1984

https://openspace.dmacc.edu/expressions/1008/thumbnail.jp

CD3ζ-based chimeric antigen receptors mediate T cell activation viacis- andtrans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy

Chimeric antigen receptors (CARs) can mediate redirected lysis of tumour cells in a major histocompatibility complex (MHC)-independent manner, thereby enabling autologous adoptive T cell therapy for a variety of malignant neoplasms. Currently, most CARs incorporate the T cell receptor (TCR) CD3ζ signalling chain; however, the precise mechanisms responsible for CAR-mediated T cell activation are unclear. In this study, we used a series of immunoreceptor tyrosine-based activation motif (ITAM)-mutant and transmembrane-modified receptors to demonstrate that CARs activate T cells both directly via the antigen-ligated signalling chain and indirectly via associated chains within the TCR complex. These observations allowed us to generate new receptors capable of eliciting polyfunctional responses in primary human T cells. This work increases our understanding of CAR function and identifies new avenues for the optimization of CAR-based therapeutic interventions

CD8+ T-­cell specificity is compromised at a defined major histocompatibility complex class I/CD8 affinity threshold

The CD8 co-receptor engages peptide-major histocompatibility complex class I (pMHCI) molecules at a largely invariant site distinct from the T-cell receptor (TCR)-binding platform and enhances the sensitivity of antigen-driven activation to promote effective CD8+ T-cell immunity. A small increase in the strength of the pMHCI/CD8 interaction (~1.5-fold) can disproportionately amplify this effect, boosting antigen sensitivity by up to two orders of magnitude. However, recognition specificity is lost altogether with more substantial increases in pMHCI/CD8 affinity (~10-fold). In this study, we used a panel of MHCI mutants with altered CD8-binding properties to show that TCR-mediated antigen specificity is delimited by a pMHCI/CD8 affinity threshold. Our findings suggest that CD8 can be engineered within certain biophysical parameters to enhance the therapeutic efficacy of adoptive T-cell transfer irrespective of antigen specificity