Alkaloidal variation in Cissampelos capensis (Menispermaceae)

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Multisite Phosphorylation Modulates the T Cell Receptor ζ-Chain Potency but not the Switchlike Response

AbstractMultisite phosphorylation is ubiquitous in cellular signaling and is thought to provide signaling proteins with additional regulatory mechanisms. Indeed, mathematical models have revealed a large number of mechanisms by which multisite phosphorylation can produce switchlike responses. The T cell antigen receptor (TCR) is a multisubunit receptor on the surface of T cells that is a prototypical multisite substrate as it contains 20 sites that are distributed on 10 conserved immunoreceptor tyrosine-based activation motifs (ITAMs). The TCR ζ-chain is a homodimer subunit that contains six ITAMs (12 sites) and exhibits a number of properties that are predicted to be sufficient for a switchlike response. We have used cellular reconstitution to systematically study multisite phosphorylation of the TCR ζ-chain. We find that multisite phosphorylation proceeds by a nonsequential random mechanism, and find no evidence that multiple ITAMs modulate a switchlike response but do find that they alter receptor potency and maximum phosphorylation. Modulation of receptor potency can be explained by a reduction in molecular entropy of the disordered ζ-chain upon phosphorylation. We further find that the tyrosine kinase ZAP-70 increases receptor potency but does not modulate the switchlike response. In contrast to other multisite proteins, where phosphorylations act in strong concert to modulate protein function, we suggest that the multiple ITAMs on the TCR function mainly to amplify subsequent signaling

Transnational labor regulation, reification and commodification: A critical review

Why does scholarship on transnational labor regulation (TLR) consistently fails to search for improvements in working conditions, and instead devotes itself to relentless efforts for identifying administrative processes, semantics, and amalgamations of stakeholders? This article critiques TLR from a pro-worker perspective, through the philosophical work of Georg Lukács, and the concepts of reification and commodification. A set of theoretically grounded criteria is developed and these are applied against selected contemporary cases of TLR. In the totality that is capitalism, reification of social relations of production conceals completely the experiences of workers. In TLR, managerialist and process-oriented scholarship is dominant, verifiable outcomes and positive improvements in conditions of employment are not sought, and worse, meaningless procedures are celebrated as positive achievements

Determining the feasibility of harvesting invasive alien plant species for energy

Woody invasive alien plants (IAPs) are a threat to South Africa’s water resources, biodiversity and land productivity. The impacts of IAPs were the main reason for the South African government to embark on a natural resource management public works programme called Working for Water (WfW), which was aimed at controlling IAPs in a cost-effective yet labour-intensive way. At the same time, the high biomass of these species presents opportunities for synergies between the clearing of IAPs and the generation of biomassbased energy. The purpose of this study was to determine the cost of harvesting and extracting, chipping, and transporting the biomass, and also to determine the financial and economic feasibility of such an exercise from a commercial perspective. Sampling of the biomass was done at 31 representative sites within the Nelson Mandela Metropolitan Municipality, South Africa. The cost of the operation was carefully monitored, documented and reported at each stage, and compared to the cost of replacing the thermal coal currently used by industry within this municipality. The project proved to be financially viable, but only when the energy entrepreneur forms a partnership with the WfW programme, and then only under specific conditions. The project has, however, very high socio-economic returns with respect to a reduction in environmental externalities and job creation.Working for Water and the Industrial Development Corporationhttp://www.sajs.co.zahb201

Determining the feasibility of harvesting invasive alien plant species for energy

Woody invasive alien plants (IAPs) are a threat to South Africa’s water resources, biodiversity and land productivity. The impacts of IAPs were the main reason for the South African government to embark on a natural resource management public works programme called Working for Water (WfW), which was aimed at controlling IAPs in a cost-effective yet labour-intensive way. At the same time, the high biomass of these species presents opportunities for synergies between the clearing of IAPs and the generation of biomassbased energy. The purpose of this study was to determine the cost of harvesting and extracting, chipping, and transporting the biomass, and also to determine the financial and economic feasibility of such an exercise from a commercial perspective. Sampling of the biomass was done at 31 representative sites within the Nelson Mandela Metropolitan Municipality, South Africa. The cost of the operation was carefully monitored, documented and reported at each stage, and compared to the cost of replacing the thermal coal currently used by industry within this municipality. The project proved to be financially viable, but only when the energy entrepreneur forms a partnership with the WfW programme, and then only under specific conditions. The project has, however, very high socio-economic returns with respect to a reduction in environmental externalities and job creation.Working for Water and the Industrial Development Corporationhttp://www.sajs.co.zahb201

Specificity of bispecific T cell receptors and antibodies targeting peptide-HLA

Tumor-associated peptide–human leukocyte antigen complexes (pHLAs) represent the largest pool of cell surface–expressed cancer-specific epitopes, making them attractive targets for cancer therapies. Soluble bispecific molecules that incorporate an anti-CD3 effector function are being developed to redirect T cells against these targets using 2 different approaches. The first achieves pHLA recognition via affinity-enhanced versions of natural TCRs (e.g., immune-mobilizing monoclonal T cell receptors against cancer [ImmTAC] molecules), whereas the second harnesses an antibody-based format (TCR-mimic antibodies). For both classes of reagent, target specificity is vital, considering the vast universe of potential pHLA molecules that can be presented on healthy cells. Here, we made use of structural, biochemical, and computational approaches to investigate the molecular rules underpinning the reactivity patterns of pHLA-targeting bispecifics. We demonstrate that affinity-enhanced TCRs engage pHLA using a comparatively broad and balanced energetic footprint, with interactions distributed over several HLA and peptide side chains. As ImmTAC molecules, these TCRs also retained a greater degree of pHLA selectivity, with less off-target activity in cellular assays. Conversely, TCR-mimic antibodies tended to exhibit binding modes focused more toward hot spots on the HLA surface and exhibited a greater degree of crossreactivity. Our findings extend our understanding of the basic principles that underpin pHLA selectivity and exemplify a number of molecular approaches that can be used to probe the specificity of pHLA-targeting molecules, aiding the development of future reagents

High-affinity CD8 variants enhance the sensitivity of pMHCI antigen recognition via low-affinity TCRs

The recognition of cell surface presented peptide-Major Histocompatibility Complex Class I (pMHCI) molecules by CD8 T-cells involves cooperative binding of the T-cell receptor (TCR) and CD8 co-receptor. CD8 T-cell antigen specificity is conferred by the TCR, whilst CD8 acts to stabilize the TCR/pMHCI complex and enhance T-cell antigen sensitivity. Earlier work has shown that the sensitivity of antigen recognition can be regulated in vitro by altering the strength of the pMHCI/CD8 interaction. Here, we characterize two CD8 variants with an enhanced affinity for MHCI that remains below the affinity threshold at which non-specific activation is observed. In model systems, expression of these CD8 variants preferentially enhanced pMHCI antigen recognition in the context of low-affinity TCRs. When combined with MHCI-restricted TCRs in primary CD4 T-cells, high affinity CD8 variants could improve T-cell functionality, without loss of antigen specificity. In primary CD8 T-cells, the introduction of high affinity CD8 enhanced T-cell activation compared to endogenous CD8 expression only, although we observed that the introduction of transgenic wild-type CD8 into primary CD8 T-cells also resulted in a similar T-cell effector function enhancement. Collectively, these findings could provide a generically applicable and immediately translatable strategy to augment the therapeutic efficacy of clinically relevant TCRs, which are already being delivered alongside wild-type CD8

Development and validation of a model to predict the 10-year risk of general practitioner-recorded COPD

There is increasing interest in the earlier detection of, and intervention in, patients at highest risk of developing chronic obstructive pulmonary disease (COPD).status: publishe

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700