Immunoproteasome-Deficiency Has No Effects on NK Cell Education, but Confers Lymphocytes into Targets for NK Cells in Infected Wild-Type Mice

Natural killer (NK) cells are part of the innate immune system and contribute to the eradication of virus infected cells and tumors. NK cells express inhibitory and activating receptors and their decision to kill a target cell is based on the balance of signals received through these receptors. MHC class I molecules are recognized by inhibitory receptors, and their presence during NK cell education influences the responsiveness of peripheral NK cells. We here demonstrate that mice with reduced MHC class I cell surface expression, due to deficiency of immunoproteasomes, have responsive NK cells in the periphery, indicating that the lower MHC class I levels do not alter NK cell education. Following adoptive transfer into wild-type (wt) recipients, immunoproteasome-deficient splenocytes are tolerated in naive but rejected in virus-infected recipients, in an NK cell dependent fashion. These results indicate that the relatively low MHC class I levels are sufficient to protect these cells from rejection by wt NK cells, but that this tolerance is broken in infection, inducing an NK cell-dependent rejection of immunoproteasome-deficient cells

Decision making around living and deceased donor kidney transplantation: a qualitative study exploring the importance of expected relationship changes

BACKGROUND: Limited data exist on the impact of living kidney donation on the donor-recipient relationship. Purpose of this study was to explore motivations to donate or accept a (living donor) kidney, whether expected relationship changes influence decision making and whether relationship changes are actually experienced. METHODS: We conducted 6 focus groups in 47 of 114 invited individuals (41%), asking retrospectively about motivations and decision making around transplantation. We used qualitative and quantitative methods to analyze the focus group transcripts. RESULTS: Most deceased donor kidney recipients had a potential living donor available which they refused or did not want. They mostly waited for a deceased donor because of concern for the donor’s health (75%). They more often expected negative relationship changes than living donor kidney recipients (75% vs. 27%, p = 0.01) who also expected positive changes. Living donor kidney recipients mostly accepted the kidney to improve their own quality of life (47%). Donors mostly donated a kidney because transplantation would make the recipient less dependent (25%). After transplantation both positive and negative relationship changes are experienced. CONCLUSION: Expected relationship changes and concerns about the donor’s health lead some kidney patients to wait for a deceased donor, despite having a potential living donor available. Further research is needed to assess whether this concerns a selected group

Pre-existing virus-specific CD8+ T-cells provide protection against pneumovirus-induced disease in mice

Pneumoviruses such as pneumonia virus of mice (PVM), bovine respiratory syncytial virus (bRSV) or human (h)RSV are closely related pneumoviruses that cause severe respiratory disease in their respective hosts. It is well-known that T-cell responses are essential in pneumovirus clearance, but pneumovirus-specific T-cell responses also are important mediators of severe immunopathology. In this study we determined whether memory- or pre-existing, transferred virus-specific CD8 + T-cells provide protection against PVM-induced disease. We show that during infection with a sublethal dose of PVM, both natural killer (NK) cells and CD8 + T-cells expand relatively late. Induction of CD8 + T-cell memory against a single CD8 + T-cell epitope, by dendritic cell (DC)-peptide immunization, leads to partial protection against PVM challenge and prevents Th2 differentiation of PVM-induced CD4 T-cells. In addition, adoptively transferred PVM-specific CD8 + T-cells, covering the entire PVM-specific CD8 + T-cell repertoire, provide partial protection from PVM-induced disease. From these data we infer that antigen-specific memory CD8 + T-cells offer significant protection to PVM-induced disease. Thus, CD8 + T-cells, despite being a major cause of PVM-associated pathology during primary infection, may offer promising targets of a protective pneumovirus vaccine

Stable isotope tagging of epitopes: a highly selective strategy for the identification of major histocompatibility complex class I-associated peptides induced upon viral infection.

Identification of peptides presented in major histocompatibility complex (MHC) class I molecules after viral infection is of strategic importance for vaccine development. Until recently, mass spectrometric identification of virus-induced peptides was based on comparative analysis of peptide pools isolated from uninfected and virus-infected cells. Here we report on a powerful strategy aiming at the rapid, unambiguous identification of naturally processed MHC class I-associated peptides, which are induced by viral infection. The methodology, stable isotope tagging of epitopes (SITE), is based on metabolic labeling of endogenously synthesized proteins during infection. This is accomplished by culturing virus-infected cells with stable isotope-labeled amino acids that are expected to be anchor residues (i.e. residues of the peptide that have amino acid side chains that bind into pockets lining the peptide-binding groove of the MHC class I molecule) for the human leukocyte antigen allele of interest. Subsequently these cells are mixed with an equal number of non-infected cells, which are cultured in normal medium. Finally peptides are acid-eluted from immunoprecipitated MHC molecules and subjected to two-dimensional nanoscale LC-MS analysis. Virus-induced peptides are identified through computer-assisted detection of characteristic, binomially distributed ratios of labeled and unlabeled molecules. Using this approach we identified novel measles virus and respiratory syncytial virus epitopes as well as infection-induced self-peptides in several cell types, showing that SITE is a unique and versatile method for unequivocal identification of disease-related MHC class I epitopes

Generation of Vorticity Near Topography: Anticyclones in the Caribbean Sea

Mesoscale anticyclonic eddies dominate the sea-surface height variability in the Caribbean Sea. Although it is well established that these anticyclones are formed near the eastern boundary of the Caribbean Sea, which is demarcated by the Lesser Antilles, the source of their anticyclonic vorticity remains unclear. To gain insight into this source, we analyze the fluxes of vorticity into the Caribbean at its eastern boundary using a high-resolution numerical model. We find that the anticyclonic vorticity in the eastern Caribbean Sea predominantly originates from regions where intense ocean currents flow close to the Lesser Antilles. More specifically, St. Lucia and Grenada are hotspots for vorticity generation. The local generation rate scales with the amplitude of the volume transport through the passages between these islands. This finding is in contrast with the view that anticyclonic North Brazil Current (NBC) rings in the Atlantic Ocean are the main source of anticyclonic vorticity in the eastern Caribbean Sea. Our analyses reveal that the direct contribution of the vorticity of the NBC rings is of lesser importance than the local generation. However, the collision of upstream NBC rings with the Lesser Antilles increases the volume transport through the passages into the Caribbean Sea, so that their presence indirectly leads to enhanced local production of anticyclonic vorticity. This process is an example of the importance of vorticity generation near topography, which is ubiquitous in the oceans, and expected to be important whenever currents and steep topography meet

Quantifying the post-radiation accelerated brain aging rate in glioma patients with deep learning

Background and purpose: Changes of healthy appearing brain tissue after radiotherapy (RT) have been previously observed. Patients undergoing RT may have a higher risk of cognitive decline, leading to a reduced quality of life. The experienced tissue atrophy is similar to the effects of normal aging in healthy individuals. We propose a new way to quantify tissue changes after cranial RT as accelerated brain aging using the BrainAGE framework. Materials and methods: BrainAGE was applied to longitudinal MRI scans of 32 glioma patients. Utilizing a pre-trained deep learning model, brain age is estimated for all patients’ pre-radiotherapy planning and follow-up MRI scans to acquire a quantification of the changes occurring in the brain over time. Saliency maps were extracted from the model to spatially identify which areas of the brain the deep learning model weighs highest for predicting age. The predicted ages from the deep learning model were used in a linear mixed effects model to quantify aging of patients after RT. Results: The linear mixed effects model resulted in an accelerated aging rate of 2.78 years/year, a significant increase over a normal aging rate of 1 (p < 0.05, confidence interval = 2.54–3.02). Furthermore, the saliency maps showed numerous anatomically well-defined areas, e.g.: Heschl's gyrus among others, determined by the model as important for brain age prediction. Conclusion: We found that patients undergoing RT are affected by significant post-radiation accelerated aging, with several anatomically well-defined areas contributing to this aging. The estimated brain age could provide a method for quantifying quality of life post-radiotherapy

Action research and democracy

This contribution explores the relationship between research and learning democracy. Action research is seen as being compatible with the orientation of educational and social work research towards social justice and democracy. Nevertheless, the history of action research is characterized by a tension between democracy and social engineering. In the social-engineering approach, action research is conceptualized as a process of innovation aimed at a specific Bildungsideal. In a democratic approach action research is seen as research based on cooperation between research and practice. However, the notion of democratic action research as opposed to social engineering action research needs to be theorized. So called democratic action research involving the implementation by the researcher of democracy as a model and as a preset goal, reduces cooperation and participation into instruments to reach this goal, and becomes a type of social engineering in itself. We argue that the relationship between action research and democracy is in the acknowledgment of the political dimension of participation: ‘a democratic relationship in which both sides exercise power and shared control over decision-making as well as interpretation’. This implies an open research design and methodology able to understand democracy as a learning process and an ongoing experiment

Employment and ability to work after kidney transplantation in the Netherlands:The impact of preemptive versus non-preemptive kidney transplantation

Background: Work can have a major positive impact on health and wellbeing. Employment of kidney transplant recipients (KTR) of working age is much lower than in the general population. The first aim of this study was to examine the impact of a preemptive kidney transplantation (PKT) on employment, in addition to other possible influencing factors. The second aim was to explore differences in work ability, absenteeism and work performance among employed KTR with different types of transplantations. Methods: A cross-sectional survey study was conducted between 2018 and 2019 in nine Dutch hospitals. PKT as potential predictor of employment was examined. Furthermore, work ability, absenteeism and loss of work performance were compared between employed preemptive recipients with a living donor (L-PKT) and non-preemptive recipients with a living donor (L-nPKT) and with a deceased donor (D-nPKT). Results: Two hundred and twenty four KTR participated; 71% reported having paid work. Paid work was more common among PKT recipients (82% vs. 65% in L-nPKT and 55% in D-nPKT) and recipients who were younger (OR .950, 95%CI .913-.989), had no comorbidities (1 comorbidity: OR .397, 95%CI .167-.942; 2 comorbidities: OR .347, 95%CI .142-.844), had less fatigue (OR .974, 95%CI .962-.987) and had mentally demanding work tasks (only in comparison with physically demanding tasks, OR .342, 95%CI .145-.806). If recipients were employed, D-nPKT recipients worked fewer hours (mean 24.6 +/- 11.3 vs. PKT 31.1 +/- 9.6, L-nPKT 30.1 +/- 9.5) and D-nPKT and L-nPKT recipients received more often supplemental disability benefits (32 and 33.3%, respectively) compared to PKT recipients (9.9%). No differences were found for self-reported ability to work, sick leave (absenteeism) and loss of work performance with the exception of limitations in functioning at work. Conclusions: Preemptive kidney transplantation recipients with a kidney from a living donor are employed more often, work more hours per week (only in comparison with D-nPKT) and have a partial disability benefit less often than nPKT recipients. More knowledge regarding treatments supporting sustainable participation in the labor force is needed as work has a positive impact on recipients' health and wellbeing and is also beneficial for society as a whole

Data management in anthropology: the next phase in ethics governance?

Recent demands for accountability in ‘data management’ by funding agencies, universities, international journals and other academic institutions have worried many anthropologists and ethnographers. While their demands for transparency and integrity in opening up data for scrutiny seem to enhance scientific integrity, such principles do not always consider the way the social relationships of research are properly maintained. As a springboard, the present Forum, triggered by such recent demands to account for the use of ‘data’, discusses the present state of anthropological research and academic ethics/integrity in a broader perspective. It specifically gives voice to our disciplinary concerns and leads to a principled statement that clarifies a particularly ethnographic position. This position is then discussed by several commentators who treat its viability and necessity against the background of wider developments in anthropology – sustaining the original insight that in ethnography, research materials have been co‐produced before they become commoditised into ‘data’. Finally, in moving beyond such a position, the Forum broadens the issue to the point where other methodologies and forms of ownership of research materials will also need consideration

Tropical biogeomorphic seagrass landscapes for coastal protection:Persistence and wave attenuation during major storms events

The intensity of major storm events generated within the Atlantic Basin is projected to rise with the warming of the oceans, which is likely to exacerbate coastal erosion. Nature-based flood defence has been proposed as a sustainable and effective solution to protect coastlines. However, the ability of natural ecosystems to withstand major storms like tropical hurricanes has yet to be thoroughly tested. Seagrass meadows both stabilise sediment and attenuate waves, providing effective coastal protection services for sandy beaches. To examine the tolerance of Caribbean seagrass meadows to extreme storm events, and to investigate the extent of protection they deliver to beaches, we employed a combination of field surveys, biomechanical measurements and wave modelling simulations. Field surveys of sea- grass meadows before and after a direct hit by the category 5 Hurricane Irma documented that estab- lished seagrass meadows of Thalassia testudinum re- mained unaltered after the extreme storm event. The flexible leaves and thalli of seagrass and calci- fying macroalgae inhabiting the meadows were shown to sustain the wave forces that they are likely to experience during hurricanes. In addition, the seagrass canopy and the complex biogeomorphic landscape built by the seagrass meadows combine to significantly dissipate extreme wave forces, ensuring that erosion is minimised within sandy beach fore- shores. The persistence of the Caribbean seagrass meadows and their coastal protection services dur- ing extreme storm events ensures that a stable coastal ecosystem and beach foreshore is maintained in tropical regions