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A growing literature in philosophy of science focuses on the role of aesthetics in scientific practice, with the experiment recently recognized for its aesthetic value. However, the literature on aesthetics in experimentation grows out of case studies from the history of science, leaving open the question as to how contemporary scientists experience aesthetics in their experimental work. In this paper we offer the first qualitative, empirical analysis of aesthetic experiences regarding experimental practice, drawing from in-depth interviews with 215 scientists in four countries. We identify six categories of aesthetic experience we find in experimentation, their function, and new questions emerging from our study. [ABSTRACT FROM AUTHOR]

The 'Immunogenetics of Aging' project is a component introduced in the 14th International HLA and Immunogenetics Workshop (IHIW) and developed further within subsequent workshops. The aim was to determine the relevance of immunogenetic markers, focusing on HLA, cytokine genes, and some innate immunity genes, for successful aging and an increased capacity to reach the extreme limits of life-span. Within the 17th IHIW we applied Next Generation Sequencing methods to refine further HLA associations at allele level in longevity, and to extend our knowledge to additional loci such as HLA-DQA1 , HLA-DPB1 and HLA-DPA1. Analysis of relatively small number of healthy elderly and young controls from four populations showed that some HLA class I and class II alleles were significantly positively associated with healthy aging. Additionally we observed statistically significant differences in HLA allele distribution when the analysis was performed separately in elderly females and males compared to sex-matched young controls. Haplotypes, probably associated with better control of viral and malignant diseases were increased in the elderly sample. These preliminary NGS data could confirm our hypotheses that survival and longevity might be associated with selection of HLA alleles and haplotypes conferring disease resistance or susceptibility. Therefore HLA alleles and haplotypes could be informative immunogenetic markers for successful ageing. [ABSTRACT FROM AUTHOR]

This paper examines whether, and in what contexts, Duhem's and Poincaré's views can be regarded as conventionalist or structural realist. After analysing the three different contexts in which conventionalism is attributed to them—in the context of the aim of science, the underdetermination problem and the epistemological status of certain principles—I show that neither Duhem's nor Poincaré's arguments can be regarded as conventionalist. I argue that Duhem and Poincaré offer different solutions to the problem of theory choice, differ in their stances towards scientific knowledge and the status of scientific principles, making their epistemological claims substantially different. [ABSTRACT FROM AUTHOR]

Poincaré is well known for his conventionalism and structuralism. However, the relationship between these two theses and their place in Poincaré׳s epistemology of science remain puzzling. In this paper I show the scope of Poincaré׳s conventionalism and its position in Poincaré׳s hierarchical approach to scientific theories. I argue that for Poincaré scientific knowledge is relational and made possible by synthetic a priori , empirical and conventional elements, which, however, are not chosen arbitrarily. By examining his geometric conventionalism, his hierarchical account of science and defence of continuity in theory change, I argue that Poincaré defends a complex structuralist position based on synthetic a priori and conventional elements, the mind-dependence of which precludes epistemic access to mind-independent structures. [ABSTRACT FROM AUTHOR]

Abstract: MPL exon 10 mutations were the second class of mutations shown to be associated with the pathogenesis of some Philadelphia chromosome – negative myeloproliferative neoplasms (MPNs). Recently, their identification gained wide recognition in the diagnostic work-up for suspected cases of JAK2 V617F negative MPNs. Various molecular approaches have been applied, yet universally accepted method is still lacking. We aimed at development and validation of a novel bead-based liquid assay using Locked nucleic acids (LNA)-modified oligonucleotide probes for multiplexed detection of the following MPL mutations: W515L/K/A/R. Testing on both artificial plasmid constructs and on clinical samples revealed that the method was comparable in terms of specificity to direct sequencing and had a much higher sensitivity of 1% mutant alleles. This method could be successfully implemented in the diagnostic work-up for MPNs. Furthermore, this system allows further multiplexing for single-tube identification of different mutations associated with MPNs. [Copyright &y& Elsevier]

This paper examines Duhem’s concept of good sense as an attempt to support a non rule-governed account of rationality in theory choice. Faced with the underdetermination of theory by evidence thesis and the continuity thesis, Duhem tried to account for the ability of scientists to choose theories that continuously grow to a natural classification. I will examine the concept of good sense and the problems that stem from it. I will also present a recent attempt by David Stump to link good sense to virtue epistemology. I will argue that even though this approach can be useful for the better comprehension of the concept of good sense, there are some substantial differences between virtue epistemologists and Duhem. In the light of this reconstruction of good sense, I will propose a possible way to interpret the concept of good sense, which overcomes the noted problems and fits better with Duhem’s views on scientific method and motivation in developing the concept of good sense. [Copyright &y& Elsevier]

An introduction to this issue of "Studies in History & Philosophy of Modern Physics, in which the editor discusses the relativized a priori and conventionalism.

Abstract: In the present work we established a rapid, cost-effective and high-throughput method for genotyping using a multiplexed microsphere-based suspension array platform - LuminexRxMAP™ which enabled us to analyze 3 SNPs in the MBL2 gene promoter and 5′ UTR, and 3 coding SNPs exon 1 haplotypes, associated with different levels of MBL2 expression. Using this system MBL2 diversity in four different ethnic groups, namely, Asian (Japanese), Caucasian, Hispanic and African-American—assessed. Results showed significant variability in terms of allele, genotype, and haplotype distribution. Characteristic MBL haplotype patterns were defined for each ethnic group. A prevalence of haplotypes coding functional proteins capable of complement activation and pathogen opsonization was observed. Regardless of the significant diversity of individual haplotypes, a high, almost similar (25–28%) proportion of haplotypes associated with MBL deficiency was found in the four ethic groups. The proportion of individuals homozygous for the haplotypes resulting in complete MBL2 deficiency was also significant (2–10%). Considering the role of MBL2 in innate immunity and as a clinically relevant marker, the genotyping approach developed and the knowledge of the genetic variation in different ethnic groups will be relevant to future medical genetic studies. [Copyright &y& Elsevier]

Chronic allograft nephropathy (CAN) is one of the main causes of graft loss in renal transplantation. Polymorphisms with functional significance in the promoter and coding regions of cytokine genes have been suggested as a possible factor for graft rejection. The aim of this study was to investigate the impact of cytokine gene polymorphism of pro and anti-inflammatory cytokines on development of CAN in a group of renal transplant patients and donors. Eight single nucleotide polymorphisms (SNPs) including TNFA (-308), TGFB1 (cdns10, 25), IL-10 (-1082, -819, -592), IL-6 (- 174) and IFNG (+874) were analyzed in 56 patients with stable graft function (SGF), 10 with CAN and 28 kidney donors by PCR-SSP method. CAN was significantly associated with the recipient TGFB1 cod10 T/T and combination of cods 10, 25 T/T G/G genotypes (high producer), (p <0.05). Influence of patient's TNFA genotype correlated with high level of gene expression on the development of CAN was further demonstrated when the patients were stratified according to the HLA mismatches (HLA-DRB MMs). Additionally donor TNFA-308 G/A (high) and IL-6- 174 CC (low) genotypes were increased in cases with CAN. No statistically significant differences in distribution of IL-10, IL-6 and IFNG genotypes between recipients with SGF and CAN were found. In conclusion our data suggest that the high producer genotype of profibrogenetic TGF-β1, pro-inflammatory TNF-α and genetically determined low production of immunoregulatory IL-6 cytokine might be risk factors for CAN development. [ABSTRACT FROM AUTHOR]

Although human leukocyte antigen (HLA) gene polymorphism has been investigated in many populations around the world, the data on MHC class I chain-related (MIC) genes are still limited. The present study is aimed to analyze the allelic polymorphism of MICA and MICB genes and haplotype associations with HLA-B locus in 132 healthy, unrelated individuals from the Bulgarian population by next generation sequencing (NGS). A total of 36 MICA and 16 MICB alleles were observed with the highest frequency detected for MICA*008:01 (17.1%) and MICB*005:02 (32.4%). Further, two and three-loci haplotype frequencies and pairwise linkage disequilibrium were estimated. Highly significant global linkage disequilibrium was found between either HLA-B and MICA and MICB genes. This is the first study on MICA and MICB allelic polymorphism, linkage disequilibrium, and haplotype polymorphism in the Bulgarian population. These results will allow for better characterization of the genetic heterogeneity of the Bulgarian population and could contribute to further analyses on MICA and MICB clinical significance. [ABSTRACT FROM AUTHOR]

• HLA class I alleles (most notably HLA-B*35:01) can restrict the development of myeloproliferative neoplasms harboring JAK2 V617F driver mutation. • MPN stem cells can escape HLA-mediated immunoediting through downregulation of HLA class I expression. • Some therapeutic agents can up-regulate HLA class I expression in MPN stem cells. Human leukocyte antigen class I (HLA-I) genotype has been found to influence cancer development through the presentation of mutational neoepitopes. However, our understanding of its effect on the development of myeloproliferative neoplasms (MPNs) remains limited. We aimed to elucidate the putative protective role of HLA-I alleles in the development of JAK2 V617F-driven MPNs using a population genetics approach. The variability of the HLA-I genotype had no effect on the presence of JAK2 V617F mutation. However, three alleles were found to be inversely correlated with the presence of JAK2 V617F mutation: HLA-A*02:01 (p = 0.036), HLA-B*35:01 (p = 0.017), and HLA-C*15:02 (p = 0.033). The HLA-B*35:01 allele was predicted to bind to a 9-mer peptide derived from JAK2 V617F mutant protein. Gene expression analysis revealed a lower expression of HLA-A and -B in MPN CD34+ cells compared with normal CD34+ cells, which was modulated by ruxolitinib and interferon-α treatment. In summary, we provide robust evidence that specific HLA-I molecules restrict JAK2 V617F-driven oncogenesis. JAK2 V617F+ stem cells evade immune surveillance through downregulation of the HLA-I expression. Therefore, the presence of specific HLA-I alleles might be a predictive marker for response to certain immunotherapies upregulating HLA-I expression. Finally, our findings have implications in the development of mutational neoepitope-based vaccines in MPNs. Image, graphical abstract [ABSTRACT FROM AUTHOR]

In his response to my , Ian Kidd claims that my argument against Stump’s interpretation of Duhem’s concept of ‘good sense’ is unsound because it ignores an important distinction within virtue epistemology. In light of the distinction between reliabilist and responsibilist virtue epistemology, Kidd argues that Duhem can be seen as supporting the latter, which he further illustrates with a discussion of Duhem’s argument against ‘perfect theory’. I argue that no substantive argument is offered to show that the distinction is relevant and can establish that Duhem’s ‘good sense’ can be understood within responsibilist virtue epistemology. I furthermore demonstrate that Kidd’s attempt to support his contention relies on a crucial misreading of Duhem’s general philosophy of science, and in doing so highlight the importance of understanding ‘good sense’ in its original context, that of theory choice. [Copyright &y& Elsevier]

In the present study we analyzed the relevance of HLA class II in JAK2 V617F-positive (JAK2 V617F+) myeloproliferative neoplasms (MPNs) focusing on genotype diversity, associations with specific alleles and haplotypes and the level of gene expression. One hundred and thirty-nine JAK2 V617F+ MPN patients and 1083 healthy controls, typed by Next generation sequencing (NGS) were included in the study. Multivariate generalized linear models with age as a covariate were applied for analysis of HLA-II allele and haplotype associations. Publicly available gene expression datasets were used to analyze HLA-II pathway genes expression in CD34+ stem cells (SCs) from MPN patients and healthy controls. We did not observe differences in HLA evolutionary divergence (HED) between JAK2 V617F+ MPNs and healthy controls. Two alleles: HLA-DPB1*03:01, DQB1*04:02 and 4 haplotypes: DPB1*02:01-DQA1*05:05-DQB1*03:01-DRB1*11:01 , DPB1*04:02-DQA1*05:05-DQB1*03:01-DRB1*11:03 , DPB1*02:01-DQA1*01:04-DQB1*05:03-DRB1*14:04 , and DPB1*04:01-DQA1*03:01-DQB1*03:02-DRB1*04:01 had significantly lower frequency in MPN patients compared to controls. Additionally, we observed HLA-II alleles and haplotypes with statistically higher frequencies in JAK2 V617F+ patients. Differential gene expression analysis showed down-regulation of HLA-DRB1, -DRA, -DMA, -DMB, -DOA,-DRB4, CIITA , and CD74 genes in JAK2 V617F+ MPN CD34+ SCs as compared to normal CD34 + SCs. In conclusion, this study provides evidence for the pleiotropic effects of HLA-II genes in JAK2 V617F-driven MPNs. [ABSTRACT FROM AUTHOR]

Point cloud data are important sources for 3D geo-information. An inventory of the point cloud data management user requirements has been compiled using structured interviews with users from different background: government, industry and academia. Based on these requirements a benchmark has been developed to compare various point cloud data management solutions with regard to functionality and performance. The main test dataset is the second national height map of the Netherlands, AHN2, with 6–10 samples for every square meter of the country, resulting in 640 billion points. At the database level, a data storage model based on grouping the points in blocks is available in Oracle and PostgreSQL. This model is compared with the ‘flat table’ model, where each point is stored in a table row, in Oracle, PostgreSQL and the column-store MonetDB. In addition, the commonly used file-based solution Rapidlasso LAStools is used for comparison with the database solutions. The results of executing the benchmark on different platforms are presented as obtained during the increasingly challenging stages with more functionality and more data: mini (20 million points), medium (20 billion points), and full benchmark (the complete AHN2). During the design, the implementation and the execution of the benchmarks, a number of point cloud data management improvements were proposed and partly tested: Morton/Hilbert code for ordering data (especially in flat model), two algorithms for parallel query execution, and a unique vario-scale LoD data organization avoiding the density jumps of the well-known discrete LoD data organizations. [ABSTRACT FROM AUTHOR]

In order to clarify immunogenetic markers contributing to successful aging, HLA and cytokine gene profiles were analyzed in healthy elderly Bulgarians. Family segregation analysis was performed to define combined effect of haplotypes and immunophenotype profiles. The results of this study did not reveal any statisticaly significant allele and haplotype frequency differences between elderly and control group. In families with two generations longevity members we did not observed HLA alleles and haplotypes associated with autoimmunity. IL-10 genotype −1082G/A, −819 C/C, −592 C/C, related to the intermediate production, was positively associated, while genotype −1082A/A, −819 C/T, −592 C/A, related to the low level of production, was negatively associated with longevity in Bulgarians. This effect was modulated by IL-6 and IFNγ genotypes associated with the low level of these pro-inflammatory cytokines. Immunophenotypic studies indicated lower relative and absolute numbers of CD3+8+, CD8+28+ and CD8+57+ cells in elderly people. Analysis in familes showed that although most pronounced in the elderly group, lower numbers of CD8+ T cells were also found in middle aged and young members of the families compared to the age matched controls. A progressive CD8+28+ cell subsets decline was seen with aging. In addition, we did not observed the ‘immune risk phenotype’ which is a marker of an increased inflammatory activity. Based on the results of this study, it seems reasonable to suggest that a combination of specific immunogenetic and immunophenotype profiles could contribute to the successful aging and to maintaining healthy status in elderly. [Copyright &y& Elsevier]

Abstract The 17th International HLA and Immunogenetics Workshop (IHIW) organizers conducted a Pilot Study (PS) in which 13 laboratories (15 groups) participated to assess the performance of the various sequencing library preparation protocols, NGS platforms and software in use prior to the workshop. The organizers sent 50 cell lines to each of the 15 groups, scored the 15 independently generated sets of NGS HLA genotyping data, and generated "consensus" HLA genotypes for each of the 50 cell lines. Proficiency Testing (PT) was subsequently organized using four sets of 24 cell lines, selected from 48 of 50 PS cell lines, to validate the quality of NGS HLA typing data from the 34 participating IHIW laboratories. Completion of the PT program with a minimum score of 95% concordance at the HLA-A , HLA-B , HLA-C , HLA-DRB1 and HLA-DQB1 loci satisfied the requirements to submit NGS HLA typing data for the 17th IHIW projects. Together, these PS and PT efforts constituted the 17th IHIW Quality Control project. Overall PT concordance rates for HLA-A , HLA-B , HLA-C , HLA-DPA1 , HLA-DPB1 , HLA-DQA1 , HLA-DQB1 , HLA-DRB1 , HLA-DRB3 , HLA-DRB4 and HLA-DRB5 were 98.1%, 97.0% and 98.1%, 99.0%, 98.6%, 98.8%, 97.6%, 96.0%, 99.1%, 90.0% and 91.7%, respectively. Across all loci, the majority of the discordance was due to allele dropout. The high cost of NGS HLA genotyping per experiment likely prevented the retyping of initially failed HLA loci. Despite the high HLA genotype concordance rates of the software, there remains room for improvement in the assembly of more accurate consensus DNA sequences by NGS HLA genotyping software. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to define the incidence, dynamics, and profiles of anti–human leukocyte antigen antibodies (HLA-Abs) produced after kidney transplantation and their impact on graft outcome. A total of 72 first cadaver donor kidney recipients were prospectively monitored for the development of HLA-Abs using bead-based flow-cytometry assays (One Lambda FlowPRA tests). Sixteen recipients (22.2%) developed HLA-Abs after transplantation (class I, n = 7; class I+II, n = 6; class II, n = 3), in most cases (81.25%) within the first 2 weeks posttransplantation. A strong association between alloantibody presence and delayed graft function (Chi-square = 7.659, p < 0.01), acute rejection (Chi-square = 14.504, p < 0.001), chronic rejection (Chi-square = 12.84, p < 0.001), and graft loss (Chi-square = 20.283, p < 0.001) was found. Patients with higher alloantibody titers experienced acute rejections and even early graft loss, compared with those with lower titers for whom chronic rejections were more common. Immunologic complications occurred in recipients with both donor-specific and cross-reacting groups or non–donor-specific antibodies alone. A positive correlation (Pearson correlation, 0.245; p < 0.05) between HLA class I amino acid triplet incompatibility and alloantibody production was observed, mainly resulting from immunogenic triplotypes. Given the results obtained in this study, an alloantibody testing algorithm has been designed and implemented for routine monitoring and to define optimally the alloantibody reactivity in kidney transplant recipients. [Copyright &y& Elsevier]