Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation.

Celiac disease driven by an antigluten T cell response is strongly associated with the histocompatibility antigen HLA-DQ2.5 but is barely associated with HLA-DQ2.2. Yet these molecules have very similar peptide-binding motifs and both present gluten T cell epitopes. We found that DQ2.5(+) antigen-presenting cells (APCs) had greater stability of bound peptides and protracted gluten presentation relative to that of DQ2.2(+) cells. The improved ability of DQ2.5 to retain its peptide cargo can be ascribed to a polymorphism of DQalpha22 whereby DQ2.5 (tyrosine) can establish a hydrogen bond to the peptide main chain but DQ2.2 (phenylalanine) cannot. Our findings suggest that the kinetic stability of complexes of peptide and major histocompatibility complex (MHC) is of importance for the association of HLA with disease.

Induction of the BIM Short Splice Variant Sensitizes Proliferating NK Cells to IL-15 Withdrawal.

Adoptive transfer of allogeneic NK cells holds great promise for cancer immunotherapy. There is a variety of protocols to expand NK cells in vitro, most of which are based on stimulation with cytokines alone or in combination with feeder cells. Although IL-15 is essential for NK cell homeostasis in vivo, it is commonly used at supraphysiological levels to induce NK cell proliferation in vitro. As a result, adoptive transfer of such IL-15-addicted NK cells is associated with cellular stress because of sudden cytokine withdrawal. In this article, we describe a dose-dependent addiction to IL-15 during in vitro expansion of human NK cells, leading to caspase-3 activation and profound cell death upon IL-15 withdrawal. NK cell addiction to IL-15 was tightly linked to the BCL-2/BIM ratio, which rapidly dropped during IL-15 withdrawal. Furthermore, we observed a proliferation-dependent induction of BIM short, a highly proapoptotic splice variant of BIM in IL-15-activated NK cells. These findings shed new light on the molecular mechanisms involved in NK cell apoptosis following cytokine withdrawal and may guide future NK cell priming strategies in a cell therapy setting.

Spatiotemporal Resolution of Rab9 and CI-MPR Dynamics in the Endocytic Pathway.

Rab9 is a small GTPase that localizes to the trans-Golgi Network (TGN) and late endosomes. Its main function has long been connected to the recycling of mannose-6-phosphate receptors (MPRs). However, recent studies link Rab9 also to autophagy and lysosome biogenesis. In this paper, using confocal imaging, we characterize for the first time the live dynamics of the Rab9 constitutively active mutant, Rab9Q66L. We find that it localizes predominantly to late endosomes and that its expression in HeLa cells disperses TGN46 and cation-independent (CI-MPR) away from the Golgi yet, has no effect on the retrograde transport of CI-MPR. We also show that CI-MPR and Rab9 enter the endosomal pathway together at the transition stage between early, Rab5-positive, and late, Rab7a-positive, endosomes. CI-MPR localizes transiently to separate domains on these endosomes, where vesicles carrying CI-MPR attach and detach within seconds. Taken together, our results demonstrate that Rab9 mediates the delivery of CI-MPR to the endosomal pathway, entering the maturing endosome at the early-to-late transition.

The human-specific invariant chain isoform Iip35 modulates Iip33 trafficking and function.

The invariant chain (Ii) is a multifunctional protein, which has an essential role in the assembly and transport of major histocompatibility complex class II (MHC II) molecules. From a single gene, Ii is synthesized as four different isoforms: Iip33, Iip35, Iip41 and Iip43. Iip35 and Iip43 are specific to humans, and are formed due to an upstream alternative translation site, resulting in an N-terminal extension of 16 amino acids. This extension harbors a strong endoplasmic reticulum (ER) retention motif. Consequently, Iip35 or Iip43 expressed alone are retained in the ER, whereas Iip33 and Iip41 rapidly traffic to the endosomal pathway. Endogenously expressed, the four isoforms form mixed heterotrimers in the ER; however, mainly due to the absence of the Iip35/p43 isoforms in mice, little is known about how they influence general Ii function. In this study, we have co-expressed Iip33 and Iip35 in human cells with and without MHC II to gain a better understanding of how Iip35 isoform influences the cellular properties of Iip33. We find that Iip35 significantly affects the properties of Iip33. In the presence of Iip35, the transport of Iip33 out of the ER is delayed, its half-life is dramatically prolonged and its ability to induce enlarged endosomes and delayed endosomal maturation is abrogated.

The Paintings Reveal the Story: Case Study of a Well-Known Swedish Artist Suffering from Alzheimer's Disease.

Background: Creativity is a multifaceted, complex, activity, and as such is an overarching function of the brain rather than being confined to a specific structure or region.Alzheimer's disease effects several cognitive domains involved in the creative process of producing art. Objective: We analyze the art of a well-known Swedish visual artist who suffered from Alzheimer's disease to determine if, and in what way, his art and creative process might have been influenced by the disease. Methods: We compared his artistic process and artwork along with information from his spouse, medical r ecords, and cognitive tests as well as reviews of exhibitions written by art critics. Results: We show that not only did the artist continue to produce artwork well into a major decline in cognitive function, according to commonly used tests, but he could continue to do so for even longer with some assistance from his spouse. However, the artwork changed considerably as the disease progressed. We hypothesize that there is a substantial lack of representation of creative ability and function in cognitive tests. Conclusions: Signs of the Alzheimer's disease can be seen in the early artwork if viewed by critics and those with more specialized knowledge into the artist's production. Further analysis of the complex interaction between complex neural activities, such as artistic creativity, and cognitive diseases is warranted and might provide insight in the field of neurological degenerative disease.

Tumor growth inhibition and immune system activation following treatment with thorium-227 conjugates and PD-1 check-point inhibition in the MC-38 murine model.

Targeted thorium-227 conjugates comprise the combination of a monoclonal antibody with specificity for a tumor cell antigen and a 3,2-HOPO chelator enabling complexation of thorium-227 (Th-227). The radiolabeled conjugate functions as an effective delivery system of alpha-particle radiation to the surface of the tumor cell inducing difficult to repair complex DNA damage and cell death. In addition, the mechanism of action of targeted alpha therapy (TAT) appears to involve a significant component linked to stimulation of the immune system. We report herein evidence of immune activation and long-lasting immune protection of a TAT in a syngeneic model using the MC-38 murine cell line. Firstly, MC-38 cells were irradiated ex vivo with the thorium labeled antibody before subcutaneous implantation into mice. These mice were then rechallenged with MC-38 cells contra-laterally. In the group receiving irradiated cells, 9 out of 10 animals had no measurable tumor growth compared to aggressive tumor growth in the control group. Secondly, in an efficacy study, 500 kBq/kg of thorium labeled antibody alone or in combination with PD-1 checkpoint inhibitor gave statistically significant tumor growth inhibition compared to vehicle control. Animals with no measurable tumors were once again rechallenged contra-laterally with MC-38 cells. The re-growth of tumors was significantly delayed (approx. 60 days) in the treatment group compared to age-matched controls (approx. 30 days) in the monotherapy group. Interestingly, in the TAT/ PD-1 combination group no re-growth was observed demonstrating the potential of combining a TAT with checkpoint inhibition therapy. Finally, tumors were excised from treated mice and analyzed by flow cytometry and immunohistochemistry (IHC). Analysis revealed significant infiltration of CD8+ T-cells and mature dendritic cells compared to vehicle controls. Together these results indicated that an ongoing immune response from treatment with alpha radiation could be enhanced by check-point inhibition.

Immunostimulatory effects of targeted thorium-227 conjugates as single agent and in combination with anti-PD-L1 therapy.

BACKGROUND: Targeted thorium-227 conjugates (TTCs) are an emerging class of targeted alpha therapies (TATs). Their unique mode of action (MoA) is the induction of difficult-to-repair clustered DNA double-strand breaks. However, thus far, their effects on the immune system are largely unknown. Here, we investigated the immunostimulatory effects of the mesothelin-targeted thorium-227 conjugate (MSLN-TTC) in vitro and in vivo in monotherapy and in combination with an inhibitor of the immune checkpoint programmed death receptor ligand 1 (PD-L1) in immunocompetent mice. METHODS: The murine cell line MC38 was transfected with the human gene encoding for MSLN (hMSLN) to enable binding of the non-cross-reactive MSLN-TTC. The immunostimulatory effects of MSLN-TTC were studied in vitro on human cancer cell lines and MC38-hMSLN cells. The efficacy and MoA of MSLN-TTC were studied in vivo as monotherapy or in combination with anti-PD-L1 in MC38-hMSLN tumor-bearing immunocompetent C57BL/6 mice. Experiments were supported by RNA sequencing, flow cytometry, immunohistochemistry, mesoscale, and TaqMan PCR analyses to study the underlying immunostimulatory effects. In vivo depletion of CD8+ T cells and studies with Rag2/Il2Rg double knockout C57BL/6 mice were conducted to investigate the importance of immune cells to the efficacy of MSLN-TTC. RESULTS: MSLN-TTC treatment induced upregulation of DNA sensing pathway transcripts (IL-6, CCL20, CXCL10, and stimulator of interferon genes (STING)-related genes) in vitro as determined by RNASeq analysis. The results, including phospho-STING activation, were confirmed on the protein level. Danger-associated molecular pattern molecules were upregulated in parallel, leading to dendritic cell (DC) activation in vitro. MSLN-TTC showed strong antitumor activity (T:C 0.38, p<0.05) as a single agent in human MSLN-expressing MC38 tumor-bearing immunocompetent mice. Combining MSLN-TTC with anti-PD-L1 further enhanced the efficacy (T:C 0.08, p<0.001) as evidenced by the increased number of tumor-free surviving animals. MSLN-TTC monotherapy caused migration of CD103+ cDC1 DCs and infiltration of CD8+ T cells into tumors, which was enhanced on combination with anti-PD-L1. Intriguingly, CD8+ T-cell depletion decreased antitumor efficacy. CONCLUSIONS: These in vitro and in vivo data on MSLN-TTC demonstrate that the MoA of TTCs involves activation of the immune system. The findings are of relevance for other targeted radiotherapies and may guide clinical combination strategies.

Comparing exponential race and signal detection models of encoding stimuli into visual short-term memory.

The exponential race model embodied in the theory of visual attention (TVA) and the power law generalization of the sample size model (SSPL) provide competing accounts of the mechanisms that determine how exposure duration, set size, and attention influence how many items enter visual short-term memory (VSTM). In the exponential race model, items compete for entry into VSTM in a processing race with exponentially distributed processing times. The most recent version of the sample size model assumes that target sensitivity measured by d' increases monotonically as a function of exposure duration and decreases as a power function of set size. Here we compare the two models in a new experiment with letters and Gabor patches and with data from five previously published experiments. This was done by applying TVA to the two-alternative forced-choice method (2AFC), which forms the basis of the experimental work on the sample size model. Both models fitted individual participants' proportions of correct trials quite well, and overall the fits by the two models were almost indistinguishable. This was confirmed by formal pairwise comparison of TVA and SSPL by the Akaike information criterion and the Bayesian information criterion measures. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Common mechanisms in apparent motion perception and visual pattern matching.

Common mechanisms in apparent motion perception and visual pattern matching. Scandinavian Journal of Psychology, 50, 526-534.There are close functional similarities between apparent motion perception and visual pattern matching. In particular, striking functional similarities have been demonstrated between perception of rigid objects in apparent motion and purely mental transformations of visual size and orientation used in comparisons of objects with respect to shape but regardless of size and orientation. In both cases, psychophysical data suggest that differences in visual size are resolved as differences in depth, such that transformation of size is done by translation in depth. Furthermore, the process of perceived or imagined translation appears to be stepwise additive such that a translation over a long distance consists of a sequence of smaller translations, the durations of these steps being additive. Both perceived and imagined rotation also appear to be stepwise additive, and combined transformations of size and orientation appear to be done by alternation of small steps of pure translation and small steps of pure rotation. The functional similarities suggest that common mechanisms underlie perception of apparent motion and purely mental transformations. In line with this suggestion, functional brain imaging has isolated neural structures in motion area MT used in mental transformation of size.

Living with dementia with Lewy bodies: an interpretative phenomenological analysis.

OBJECTIVE: To explore the subjective experience of living with dementia with Lewy bodies (DLB). DESIGN: A qualitative study of in-depth interviews using interpretative phenomenological analysis. SETTING: A memory clinic in Malmö, southern Sweden. PARTICIPANTS: A purposive sample of five male participants with DLB between the ages of 78 and 88 years and disease duration of 1.5-7 years. RESULTS: Three themes were identified in relation to the participants' experiences of living with DLB: (1) disease impact, in terms of symptom experience and restricted participation and activities; (2) self-perception and coping strategies; (3) importance of others, such as healthcare, family and friends. CONCLUSIONS: This study provides a broad insight into the first-hand experience of living with DLB and how it compares with other dementia types. Findings highlight factors characterising the disease experience and well-being, and how persons with DLB address challenges arising secondary to disease. These findings are important for both research and clinical practice, demonstrating the feasibility of direct involvement of DLB persons in identifying important aspects of care, which include improved healthcare services.

Severe aortic regurgitation after implantation of a sutureless valve prosthesis using an automatic knot fastener device.

We report the case of severe aortic regurgitation 8 months after implantation of a 25-mm sutureless pericardial aortic valve prosthesis. On echocardiography, the regurgitation was suspected to be paravalvular. The sutureless prosthesis had been implanted using an automatic knot fastener device, which renders the suture tails less pliable because of the metal clip that is crimped around the suture. The patient was reoperated, a paravalvular leak was not observed. The sutureless prosthesis was explanted and a conventional biologic valve prosthesis was implanted instead. On examination of the explanted valve prosthesis, a perforation was observed in one of the leaflets. The leaflet perforation was in alignment with one of the knots produced by the automatic knot fastener. Obviously, the leaflet had hit the knot repeatedly which had caused the perforation. We conclude that knots produced by an automatic fastener device have the potential to cause leaflet perforation.

Activation in the MT-complex during visual perception of apparent motion and temporal succession.

Previous studies have shown that MT (i.e., the MT-complex) is activated during visual perception of apparent motion. To further explore the function of MT, we measured activation in MT by positron emission tomography (PET) using a broad range of stroboscopic stimulus events in which (a) the frame rate was so fast that observers perceived stimulus frames as simultaneous, (b) the frame rate was slower and generated compelling impressions of apparent motion, or (c) the frame rate was so slow that observers perceived temporal succession (successive views of the same objects at different locations) instead of motion. As expected, the simultaneity condition showed no activation (reliable increase in regional cerebral blood flow, rCBF) in MT whereas the motion condition showed activation in both left and right MT. However, the succession condition showed even stronger activation in left and right MT than did the motion condition. MT seems implicated in perception of retinal stimuli as successive views of the same object at different locations whether or not the views are connected by apparent motion.

Independent encoding of colors and shapes from two stimuli.

Observers were presented with brief exposures of pairs of colored objects (letters) and asked to report both the color and the shape of each object. Several observers showed strikingly clear evidence of nearly perfect stochastic independence between reports of the four features (two colors and two shapes). For instance, the probability that the shape of a given object could be reported seemed independent of (a) whether the color of the object could be reported and (b) whether features of the other object could be reported. Such stochastic independence is predicted by many parallel-processing models (e.g., Bundesen, 1990). However, the results are difficult to reconcile with simple serial models in which the encoding of one object is completed before the encoding of another object is begun.

[The working brain--how does it look like?]. / Den arbejdende hjerne--hvordan kan den se ud?

Numerous brain functions, such as awareness of surroundings, control of movements, thoughts, and memory have always been a kind of mystery, which has provoked human curiosity and thus inspired research in many areas. The present paper gives an overview on imaging research of the human brain's functions. The historical progress is briefly reviewed with the emphasis on major Danish contributions. The major methods of mapping brain functions and their biological basis are mentioned. These methods are positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). They are highly technological and generate enormous amounts of data. Thus, data analysis will per se be a research area in brain imaging. Finally, several examples of the authors' results on functional activation are dealt with. These examples aim to illustrate the research area and its contribution to our increased knowledge of the working brain.

Deconstructing mental rotation.

A random walk model of the classical mental rotation task is explored in two experiments. By assuming that a mental rotation is repeated until sufficient evidence for a match/mismatch is obtained, the model accounts for the approximately linearly increasing reaction times (RTs) on positive trials, flat RTs on negative trials, false alarms and miss rates, effects of complexity, and for the number of eye movement switches between stimuli as functions of angular difference in orientation. Analysis of eye movements supports key aspects of the model and shows that initial processing time is roughly constant until the first saccade switch between stimulus objects, while the duration of the remaining trial increases approximately linearly as a function of angular discrepancy. The increment results from additive effects of (a) a linear increase in the number of saccade switches between stimulus objects, (b) a linear increase in the number of saccades on a stimulus, and (c) a linear increase in the number and in the duration of fixations on a stimulus object. The fixation duration increment was the same on simple and complex trials (about 15 ms per 60°), which suggests that the critical orientation alignment take place during fixations at very high speed.

Differential regulation of Rab GTPase expression in monocyte-derived dendritic cells upon lipopolysaccharide activation: a correlation to maturation-dependent functional properties.

The regulation of Rab expression to modulate cellular function has recently been proposed. Dendritic cells are a prototypic example of cells that drastically alter their function in response to environmental cues by reducing endocytosis, secreting cytokines, changing surface protein repertoires and altering morphology and migration. This is not a binary event, but is subject to fluctuations through the activation process, termed maturation. Consequently, DCs transiently increase endocytosis and production of major histocompatibility complex class II molecules, and secrete inflammatory cytokines in infected tissues before migrating to secondary lymph nodes and releasing T cell polarizing factors. All these cellular processes rely on intracellular membrane transport, which is regulated by Rab family GTPases and their diverse effectors. Here we examine how the Rabs likely to be involved in these functions are regulated throughout DC maturation. We find that Rab expression is altered upon lipopolysaccharide-induced activation, and discuss how this correlates to the reported functions of these cells during maturation.

Differential regulation of MHC II and invariant chain expression during maturation of monocyte-derived dendritic cells.

DCs are potent initiators of adaptive immune responses toward invading pathogens. Upon reception of pathogenic stimuli, DCs initiate a complex differentiation program, culminating in mature DCs with an extreme capacity to activate naïve T cells. During this maturation, DCs reduce the synthesis and turnover of MHC II molecules. This allows for a stable population of MHC II, presenting peptides captured at the time and place of activation, thus provoking specific immune responses toward the activating pathogen. The efficient loading of antigenic peptides onto MHC II is vitally dependent on the accessory molecule Ii, which aids in the assembly of the MHC II α- and ß-chains in the ER and directs their trafficking to the endocytic compartments, where they encounter endocytosed antigen. However, Ii plays additional roles in DC function by influencing migration, antigen uptake, and processing. To examine the biosynthetic background for diverse Ii functions in DCs, we investigated mRNA and protein levels of Ii compared with MHC II in human moDCs during maturation using various stimuli. We find that the production of Ii did not correlate with that of MHC II and that mature DCs maintain abundant levels of Ii despite a reduced production of new MHC II.

Forgetting to forget: on the duration of voluntary suppression of neutral and emotional memories.

Can we control the content of our memory and forget what we do not want to think about by an act of will? If so, is forgetting temporary or permanent, and is it independent of the nature of what we wish to forget? Using Anderson and Green's (2001) "think/no-think" paradigm with neutral and emotional nouns, we found in agreement with other studies that memory for neutral words was reduced instantly upon repeated attempts at suppression. However, the effect was temporary and vanished after a period of one week, which strongly suggests that intended memory suppression interferes with immediate retrieval but does not lead to long-term forgetting. Furthermore, the amount of training that clearly reduced immediate recall of neutral items did not at all reduce recall of emotional items. This finding is in accordance with the notion that emotional items have a higher degree of salience and tend to attract more attention than neutral items.

Images of illusory motion in primary visual cortex.

Illusory motion can be generated by successively flashing a stationary visual stimulus in two spatial locations separated by several degrees of visual angle. In appropriate conditions, the apparent motion is indistinguishable from real motion: The observer experiences a luminous object traversing a continuous path from one stimulus location to the other through intervening positions where no physical stimuli exist. The phenomenon has been extensively investigated for nearly a century but little is known about its neurophysiological foundation. Here we present images of activations in the primary visual cortex in response to real and apparent motion. The images show that during apparent motion, a path connecting the cortical representations of the stimulus locations is filled in by activation. The activation along the path of apparent motion is similar to the activation found when a stimulus is presented in real motion between the two locations.

Pulmonary valve replacement for pulmonary thrombus formation after previous aortic valve replacement, Guillain-Barré syndrome and enterococcal sepsis.

Acquired disease of the pulmonary valve requiring surgery is rare. We report the case of a 70-year-old male presenting with pulmonary valve insufficiency and pulmonary emboli originating from a thrombus formation adhering to the pulmonary valve occurring despite dicoumarol anticoagulation for previous aortic valve surgery. Two years ago he experienced Guillain-Barré syndrome and one year ago enterococcal sepsis which were treated medically. Apart from a previous prolonged ICU stay no predisposing factors for right sided endocarditis could be found. The pulmonary lesion was surgically corrected with removal of the thrombus and excision of the pulmonary valve. Reconstruction of the valve and pulmonary artery was performed with a semistentless xenograft valved conduit.