In the late 1980s and early 1990s, the hunt for a transporter molecule ostensibly responsible for the translocation of peptides across the endoplasmic reticulum (ER) membrane yielded the successful ...discovery of transporter associated with antigen processing (TAP) protein. TAP is a heterodimer complex comprised of TAP1 and TAP2, which utilizes ATP to transport cytosolic peptides into the ER across its membrane. In the ER, together with other components it forms the peptide loading complex (PLC), which directs loading of high affinity peptides onto nascent major histocompatibility complex class I (MHC-I) molecules that are then transported to the cell surface for presentation to CD8+ T cells. TAP also plays a crucial role in transporting peptides into phagosomes and endosomes during cross-presentation in dendritic cells (DCs). Because of the critical role that TAP plays in both classical MHC-I presentation and cross-presentation, its expression and function are often compromised by numerous types of cancers and viruses to evade recognition by cytotoxic CD8 T cells. Here we review the discovery and function of TAP with a major focus on its role in cross-presentation in DCs. We discuss a recently described emergency route of noncanonical cross-presentation that is mobilized in DCs upon TAP blockade to restore CD8 T cell cross-priming. We also discuss the various strategies employed by cancer cells and viruses to target TAP expression or function to evade immunosurveillance - along with some strategies by which the repertoire of peptides presented by cells which downregulate TAP can be targeted as a therapeutic strategy to mobilize a TAP-independent CD8 T cell response. Lastly, we discuss TAP polymorphisms and the role of TAP in inherited disorders.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The arms race between bacteria and the phages that infect them drives the continual evolution of diverse anti-phage defences. Previously described anti-phage systems have highly varied defence ...mechanisms
; however, all mechanisms rely on protein components to mediate defence. Here we report a chemical anti-phage defence system that is widespread in Streptomyces. We show that three naturally produced molecules that insert into DNA are able to block phage replication, whereas molecules that target DNA by other mechanisms do not. Because double-stranded DNA phages are the most numerous group in the biosphere and the production of secondary metabolites by bacteria is ubiquitous
, this mechanism of anti-phage defence probably has a major evolutionary role in shaping bacterial communities.
Full text
Available for:
KISLJ, NUK, SBMB, UL, UM, UPUK
To summarize recently discovered novel cell states in rheumatoid arthritis (RA) synovium that could have important implications for disease treatment.
The use of multiomic technologies, including ...single-cell and spatial transcriptomics and mass cytometry, has led to the discovery of several novel cell states, which could have important implications for the treatment of RA. These cells can be found in patient blood, synovial fluid, or synovial tissue and span several immune cell subsets as well as stromal cell types. These diverse cell states may represent the targets of current or future therapeutics, while their fluctuations may inform the ideal timing for therapy. Future efforts are needed to implicate how each cell state functions in the pathophysiologic network within affected joints and how medications perturb each cell state and ultimately the tissue.
Multiomic molecular technologies have afforded the discovery of numerous novel cellular states in RA synovium; the next challenge will be to link these states to pathophysiology and treatment response.
The sweet smell of success in sussex Mantel, Ian K
Insurance brokers' monthly (Stourbridge, England : Online),
01/1997, Volume:
47, Issue:
1
Journal Article
To be a success as a broker, one must be prepared: prepared to work long hours, prepared to delegate, prepared to listen, prepared to promote one's business, prepared to know what the competition are ...up to, prepared to meet a challenge, and prepared for the most unreasonable of clients as well as the most desirable. This could be summed as 3M - Motivation, Marketing, and Management.
This study deals with approaches for a social-ecological friendly European bioeconomy based on biomass from industrial crops cultivated on marginal agricultural land. The selected crops to be ...investigated are: Biomass sorghum, camelina, cardoon, castor, crambe, Ethiopian mustard, giant reed, hemp, lupin, miscanthus, pennycress, poplar, reed canary grass, safflower, Siberian elm, switchgrass, tall wheatgrass, wild sugarcane, and willow. The research question focused on the overall crop growth suitability under low-input management. The study assessed: (i) How the growth suitability of industrial crops can be defined under the given natural constraints of European marginal agricultural lands; and (ii) which agricultural practices are required for marginal agricultural land low-input systems (MALLIS). For the growth-suitability analysis, available thresholds and growth requirements of the selected industrial crops were defined. The marginal agricultural land was categorized according to the agro-ecological zone (AEZ) concept in combination with the marginality constraints, so-called ‘marginal agro-ecological zones’ (M-AEZ). It was found that both large marginal agricultural areas and numerous agricultural practices are available for industrial crop cultivation on European marginal agricultural lands. These results help to further describe the suitability of industrial crops for the development of social-ecologically friendly MALLIS in Europe.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•GVAP built visibility for immunization and was an improvement over prior plans.•GVAP implementation was incomplete due to limited awareness and stakeholder buy-in.•The GVAP Monitoring & ...Evaluation/Accountability framework gave valuable guidance.•Future strategies should build greater buy-in and communicate more effectively.
The Global Vaccine Action Plan (GVAP), unanimously endorsed by the World Health Assembly in 2012, defined an ambitious strategy to improve immunization. At the end of the decade, significant progress has been made but four of the five GVAP goals are likely to be missed. This report describes a set of surveys and interviews relating to GVAP, conducted to inform the immunization strategy for the next decade.
Three surveys and two sets of semi-structured interviews were conducted from 2017 to 2019. Respondents consisted of immunization stakeholders at global, regional, and country levels, and included individuals who had been involved in the development and implementation of GVAP or its monitoring, evaluation and accountability (M&E/A) process; national immunization managers; academics; and personnel from non-governmental organizations and civil society organizations.
The surveys and interviews gave consistent results. They highlighted the value of GVAP in increasing visibility for immunization and the benefits of the GVAP M&E/A framework. The main limitations of GVAP were identified as the limited ownership by countries and other stakeholders leading to incomplete implementation of the strategy and poor accountability for achieving GVAP targets.
These results informed the review of GVAP and the development of its successor strategy, the Immunization Agenda 2030. In addition, these surveys and interviews identified two challenges in assessing the value of GVAP: the need to rely exclusively on stakeholder perspectives and difficulties in attributing benefits. These challenges are inherent in evaluating an over-arching strategy such as GVAP and should be factored into interpretation of the results.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•The M&E/A framework was a critically important element of GVAP.•It was a cyclical process of monitoring, review, and recommendations for action.•Though a step in the right direction, it failed to ...hold all stakeholders accountable.•Several GVAP goals were aspirational and unrealistic for many countries.
The Monitoring & Evaluation/Accountability (M&E/A) framework of the Global Vaccine Action Plan (GVAP) was used to report progress annually to the World Health Assembly (WHA).
Stakeholder feedback was obtained through five reviews consisting of surveys and semi-structured interviews conducted from 2017 to 2019. Participants consisted of individuals involved in the development and implementation of GVAP or its M&E/A process, national immunization managers, academics, representatives of non-governmental organizations, and civil society organizations.
The feedback was mixed and contradictory for some components, though most participants reported that the M&E/A process was a highlight of GVAP and a step in the right direction. Several of the goals and targets were considered aspirational and unrealistic for many countries. There were mixed responses on whether it promoted accountability, especially at the country level.
The mixed and contradictory views on the M&E/A processes and its impact suggested a failure of communication about its scope and intent. Though the process, especially the annual reporting to the WHA, kept immunization high on the global agenda, it failed to fully meet the expectations in promoting accountability. Engaging with countries to capture the local context in setting global goals and targets and promoting local M&E/A processes will be important to achieve accountability in the next decade.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
