PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent regulator of immune responses and a promising therapeutic target. The structure and interactions of human PD-1 are, however, ...incompletely characterized. We present the solution nuclear magnetic resonance (NMR)-based structure of the human PD-1 extracellular region and detailed analyses of its interactions with its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily topology but differs at the edge of the GFCC′ sheet, which is flexible and completely lacks a C″ strand. Changes in PD-1 backbone NMR signals induced by ligand binding suggest that, whereas binding is centered on the GFCC′ sheet, PD-1 is engaged by its two ligands differently and in ways incompletely explained by crystal structures of mouse PD-1·ligand complexes. The affinities of these interactions and that of PD-L1 with the costimulatory protein B7-1, measured using surface plasmon resonance, are significantly weaker than expected. The 3–4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the 3-fold smaller dissociation rate for PD-L2 binding. Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component. Mathematical simulations based on the biophysical data and quantitative expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1 ligation during interactions of activated T cells with antigen-presenting cells. These findings provide a rigorous structural and biophysical framework for interpreting the important functions of PD-1 and reveal that potent inhibitory signaling can be initiated by weakly interacting receptors.
Background: The inhibitory leukocyte receptor PD-1 binds two ligands, PD-L1 and PD-L2.
Results: Nuclear magnetic resonance analysis and rigorous binding and thermodynamic measurements reveal the structure of, and the mode of ligand recognition by, PD-1.
Conclusion: PD-L1 and PD-L2 bind differently to PD-1 and much more weakly than expected.
Significance: Potent inhibitory signaling can be initiated by weakly interacting receptors.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
It is now well documented that human embryonic stem cells (hESCs) can differentiate into functional cardiomyocytes. These cells constitute a promising source of material for use in drug development, ...toxicity testing, and regenerative medicine. To assess their utility as replacement or complement to existing models, extensive phenotypic characterization of the cells is required. In the present study, we used microarrays and analyzed the global transcription of hESC-derived cardiomyocyte clusters (CMCs) and determined similarities as well as differences compared with reference samples from fetal and adult heart tissue. In addition, we performed a focused analysis of the expression of cardiac ion channels and genes involved in the Ca(2+)-handling machinery, which in previous studies have been shown to be immature in stem cell-derived cardiomyocytes. Our results show that hESC-derived CMCs, on a global level, have a highly similar gene expression profile compared with human heart tissue, and their transcriptional phenotype was more similar to fetal than to adult heart. Despite the high similarity to heart tissue, a number of significantly differentially expressed genes were identified, providing some clues toward understanding the molecular difference between in vivo sourced tissue and stem cell derivatives generated in vitro. Interestingly, some of the cardiac-related ion channels and Ca(2+)-handling genes showed differential expression between the CMCs and heart tissues. These genes may represent candidates for future genetic engineering to create hESC-derived CMCs that better mimic the phenotype of the cardiomyocytes present in the adult human heart.
International Financial Reporting Standards (IFRS) is a financial reporting standard for listed corporations in more than half of the world’s countries. This wide adoption combined with its influence ...on accounting in countries that have not formally adopted it makes IFRS a remarkable case of far-reaching convergence. This paper develops a framework that integrates institutional theory and political economy and employs a discourse analytical approach to address the issue of why the Swedish accountancy profession came to accept and adopt IFRS. The analysis covers the professional debates regarding the measurement of the value of assets and liabilities in the main professional journal over the nearly two decades in which IFRS was gradually integrated into the local accounting standards on a voluntary basis prior to its formal adoption. The analysis emphasizes the combination of a pervasive international development discourse that stresses the significance of financial markets developing into a sense of inevitability and an elite portion of the accountancy profession with a vested interest in change. IFRS can be seen as a strategic professionalization project for the elite members of the accountancy profession which, combined with financial interests, led to its endorsement of the changes and alignment with forces of financialization.
Full text
Available for:
NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
The T cells scan the surface of antigen-presenting cells with their T cell receptors (TCR) in order to find and respond to specific peptide-major histocompatibility complexes (pMHC). Since mainly ...self-peptides are expressed on antigen-presenting cells, the T cells must utilize sensible mechanisms in order to quickly discriminate between self and nonself-peptides. A range of different models have been proposed to account for this process. Due to the experimental inconsistency of how T cells respond to altered peptides it has been difficult to validate the competing models. Recent models, based on the kinetic proofreading model, propose that a short life-time of the TCR/pMHC complexes may be compensated by fast rebinding of the individual molecules. Hence, both the on- and off-rate involved in the interaction between pMHCs and TCRs will determine the fate of the T cell discrimination. I here briefly review some of the proposed models on T cell discrimination and scanning, and discuss the significance of determining self-peptide kinetics to validate the different models.
The elimination of malaria in Zanzibar is highly dependent on sustained effective coverage of bed-nets to avoid malaria resurgence. The Health Belief Model (HBM) framework was used to explore the ...perceptions of malaria and bed-net use after a noticeable reduction in malaria incidence.
Nineteen in-depth interviews were conducted with female and male caretakers of children under five in North A district, Zanzibar. Deductive content analysis was used to identify meaning units that were condensed, coded and assigned to pre-determined elements of the HBM.
Awareness of malaria among caretakers was high but the illness was now seen as easily curable and uncommon. In addition to the perceived advantage of providing protection against malaria, bed-nets were also thought to be useful for avoiding mosquito nuisance, especially during the rainy season when the malaria and mosquito burden is high. The discomfort of sleeping under a net during the hot season was the main barrier that interrupted consistent bed-net usage. The main cue to using a bed-net was high mosquito density, and children were prioritized when it came to bed-net usage. Caretakers had high perceived self-efficacy and did not find it difficult to use bed-nets. Indoor Residual Spraying (IRS), which was recognized as an additional means of mosquito prevention, was not identified as an alternative for bed-nets. A barrier to net ownership was the increasingly high cost of bed-nets.
Despite the reduction in malaria incidence and the resulting low malaria risk perceptions among caretakers, the benefit of bed-nets as the most proficient protection against mosquito bites upholds their use. This, in combination with the perceived high self-efficacy of caretakers, supports bed-net usage, while seasonality interrupts consistent use. High effective coverage of bed-nets could be further improved by reinforcing the benefits of bed-nets, addressing the seasonal heat barrier by using nets with larger mesh sizes and ensuring high bed-net ownership rates through sustainable and affordable delivery mechanisms.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mice deficient for the G protein subunit Gαi2 spontaneously develop colitis, a chronic inflammatory disease associated with dysregulated T cell responses. We and others have previously demonstrated a ...thymic involution in these mice and an aberrant thymocyte dynamics. The Gαi2(-/-) mice have a dramatically reduced fraction of double positive thymocytes and an increased fraction of single positive (SP) thymocytes. In this study, we quantify a number of critical parameters in order to narrow down the underlying mechanisms that cause the dynamical changes of the thymocyte development in the Gαi2(-/-) mice. Our data suggest that the increased fraction of SP thymocytes results only from a decreased number of DP thymocytes, since the number of SP thymocytes in the Gαi2(-/-) mice is comparable to the control littermates. By measuring the frequency of T cell receptor excision circles (TRECs) in the thymocytes, we demonstrate that the number of cell divisions the Gαi2(-/-) SP thymocytes undergo is comparable to SP thymocytes from control littermates. In addition, our data show that the mature SP CD4(+) and CD8(+) thymocytes divide to the same extent before they egress from the thymus. By estimating the number of peripheral TREC(+) T lymphocytes and their death rate, we could calculate the daily egression of thymocytes. Gαi2(-/-) mice with no/mild and moderate colitis were found to have a slower export rate in comparison to the control littermates. The quantitative measurements in this study suggest a number of dynamical changes in the thymocyte development during the progression of colitis.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In order to allow for a computationally efficient estimation of radar reflections, one commonly assumes the reflecting target to be in the far-field of the sensing array, such that the impinging ...wavefront is modeled as a linear phase-shift along the array. This works well in most radar scenarios, but causes significant performance degradation for close-range radar systems, wherein the curvature of the impinging wavefront may not be neglected. In this work, we examine how the used far-field assumption limits the resulting performance, illustrating how the (misspecified) Cramér-Rao lower bound (CRLB), taking the model mismatch into account, significantly devi-ates from the true CRLB for close-range targets. We further introduce a robust estimator that allows for the waveform cur-vature, showing that this computationally efficient estimator allows for superior performance for close-range reflectors.
Manuscript Type
Empirical
Research Question/Issue
Based on an analysis of Swedish press material covering two corporate scandals, this paper reveals the institutional logic propagated by the Swedish ...press pertaining to large shareholders and the relationship between this institutional logic and the attribution of blame for the scandals to shareholders by the press.
Research Findings/Insights
The results reveal an institutional logic with a clear notion of what constitutes a “real owner,” which is reminiscent of an understanding of ownership and control prevalent in the literature before the emergence of agency theory. Real owners are associated with moderation of management, responsibility, long‐termism, and legitimate influence in the firm. In response to scandals, this institutional logic leads the Swedish press to question the “realness” of an existing controlling shareholder or, if no controlling shareholder exists, to blame the problem on the absence of a real owner.
Theoretical/Academic Implications
It is important to understand the institutional logic propagated by the press to see how the media functions as a governance mechanism, since a given institutional logic leads the media to “name and shame” in specific ways. The institutional logic propagated by the Swedish press differs from what previous research has indicated is prevalent in the US, suggesting that the media as a governance mechanism has different effects in different countries.
Practitioner/Policy Implications
This paper illustrates the importance of understanding prevalent informal norms when predicting effects of corporate governance reform and suggests that these informal aspects are highly path dependent.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A means for noninvasive measurement of transverse and longitudinal characteristics of bunched beams in synchrotrons has been developed based on high sensitivity slotted waveguide pickups. The pickups ...allow for bandwidths exceeding hundreds of MHz while maintaining good beam sensitivity characteristics. Wide bandwidth is essential to allow bunch-by-bunch measurements by means of a fast gate. The Schottky detector system is installed and successfully commissioned in the Fermilab Tevatron, Recycler and CERN LHC synchrotrons. Measurement capabilities include tune, chromaticity, and momentum spread of single or multiple beam bunches in any combination. With appropriate calibrations, emittance can also be measured by integrating the area under the incoherent tune sidebands.
Full text
Available for:
CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM, UPUK
PDF
