Models of war 1770–1830: the birth of wargames and the trade-off between realism and simplicity

The first sophisticated wargames (military board games) were developed between 1770 and 1830 and are models of military conflict. Designers of these early games experimented fruitfully with different concepts that were formulated in interaction with the external dynamics of the military systems that they tried to represent and the internal dynamics of the design process itself. The designers of early wargames were confronted with a problem that affects all models: the trade-off between realism and simplicity, which in the case of wargames amounts to the trade-off between realism and playability. I try to show how different game concepts were developed as an answer to this problem, and how these seemingly arcane concepts form a relevant topic of investigation in the history of ideas. Moreover, a direct offshoot of this conceptual experimentation between 1770 and 1830 was the ‘free’ German wargame (Kriegsspiel), which became an integral part of German operational planning in the nineteenth and twentieth centuries, thus adding another chapter to the story of the influence of ideas on human history

Of the Conduct of the Understanding, by John Locke

The editor’s General Introduction is divided into two parts. The first part, ‘Context’, discusses Locke’s analysis of the nature of error, the causes of error and the prevention and cure of error in the Conduct. His enquiry is placed in the context of his way of ideas as given in his Essay concerning Human Understanding. Locke’s two-stage way of ideas, his occupation with our mental faculties and with method form the interrelated main ingredients of his logic of ideas. There is a complicated relation of continuity and change between the content and the structure of this new logic on the one hand and the content and structure of works by both scholastic predecessors (Du Trieu, Smith, Sanderson) and novel philosophers (Descartes, Arnauld, Malebranche) on the other hand. Once this context is taken into account, the Conduct can be understood as work that has a function within the structure of Locke’s logic of ideas that runs parallel to the function of the De sophisticis elenchis in the Aristotelian Organon. The second part of the General Introduction, ‘Text’, gives a description of the relevant MSS, an overview of references to the Conduct in Locke’s correspondence, a history of the genesis of the Conduct until its first publication in 1706 in the Posthumous Works, an analysis of the evidence provided by the MSS on how the Conduct grew out of the Essay, and a statement of the principles that underlie the present editon

Hexamerization-enhanced CD20 antibody mediates complement-dependent cytotoxicity in serum genetically deficient in C9

We examined complement-dependent cytotoxicity (CDC) by hexamer formation-enhanced CD20 mAb Hx-7D8 of patient-derived chronic lymphocytic leukemia (CLL) cells that are relatively resistant to CDC. CDC was analyzed in normal human serum (NHS) and serum from an individual genetically deficient for C9. Hx-7D8 was able to kill up to 80% of CLL cells in complete absence of C9. We conclude that the narrow C5b-8 pores formed without C9 are sufficient for CDC due to efficient antibody-mediated hexamer formation. In the absence of C9, we observed transient intracellular increases of Ca2 + during CDC (as assessed with FLUO-4) that were extended in time. This suggests that small C5b-8 pores allow Ca2 + to enter the cell, while dissipation of the fluorescent signal accompanying cell disintegration is delayed. The Ca2 + signal is retained concomitantly with TOPRO-3 (viability dye) staining, thereby confirming that Ca2 + influx represents the most proximate mediator of cell death by CDC

A gene expression profile for detection of sufficient tumour cells in breast tumour tissue: microarray diagnosis eligibility

<p>Abstract</p> <p>Background</p> <p>Microarray diagnostics of tumour samples is based on measurement of prognostic and/or predictive gene expression profiles. Typically, diagnostic profiles have been developed using bulk tumour samples with a sufficient amount of tumour cells (usually >50%). Consequentially, a diagnostic results depends on the minimal percentage of tumour cells within a sample. Currently, tumour cell percentage is assessed by conventional histopathological review. However, even for experienced pathologists, such scoring remains subjective and time consuming and can lead to ambiguous results.</p> <p>Methods</p> <p>In this study we investigated whether we could use transcriptional activity of a specific set of genes instead of histopathological review to identify samples with sufficient tumour cell content. Genome-wide gene expression measurements were used to develop a transcriptional gene profile that could accurately assess a sample's tumour cell percentage.</p> <p>Results</p> <p>Supervised analysis across 165 breast tumour samples resulted in the identification of a set of 13 genes which expression correlated with presence of tumour cells. The developed gene profile showed a high performance (AUC 0.92) for identification of samples that are suitable for microarray diagnostics. Validation on 238 additional breast tumour samples indicated a robust performance for correct classification with an overall accuracy of 91 percent and a kappa score of 0.63 (95%CI 0.47–0.73).</p> <p>Conclusion</p> <p>The developed 13-gene profile provides an objective tool for assessment whether a breast cancer sample contains sufficient tumour cells for microarray diagnostics. It will improve the efficiency and throughput for diagnostic gene expression profiling as it no longer requires histopathological analysis for initial tumour percentage scoring. Such profile will also be very use useful for assessment of tumour cell percentage in biopsies where conventional histopathology is difficult, such as fine needle aspirates.</p

Characterizing steroid hormone receptor chromatin binding landscapes in male and female breast cancer

Male breast cancer (MBC) is rare and largely hormonally driven. Here, the authors examine the action of steroid hormone receptors in male and female breast cancers and find gender selective hormone receptor action that associates with the survival of MBC patients

Ambient Intelligence and Persuasive Technology: The Blurring Boundaries Between Human and Technology

The currently developing fields of Ambient Intelligence and Persuasive Technology bring about a convergence of information technology and cognitive science. Smart environments that are able to respond intelligently to what we do and that even aim to influence our behaviour challenge the basic frameworks we commonly use for understanding the relations and role divisions between human beings and technological artifacts. After discussing the promises and threats of these technologies, this article develops alternative conceptions of agency, freedom, and responsibility that make it possible to better understand and assess the social roles of Ambient Intelligence and Persuasive Technology. The central claim of the article is that these new technologies urge us to blur the boundaries between humans and technologies also at the level of our conceptual and moral frameworks

Antibody Engineering & Therapeutics 2016: The Antibody Society's annual meeting, December 11–15, 2016, San Diego, CA

ABSTRACT Antibody Engineering & Therapeutics, the largest meeting devoted to antibody science and technology and the annual meeting of The Antibody Society, will be held in San Diego, CA on December 11-15, 2016. Each of 14 sessions will include six presentations by leading industry and academic experts. In this meeting preview, the session chairs discuss the relevance of their topics to current and future antibody therapeutics development. Session topics include bispecifics and designer polyclonal antibodies; antibodies for neurodegenerative diseases; the interface between passive and active immunotherapy; antibodies for non-cancer indications; novel antibody display, selection and screening technologies; novel checkpoint modulators / immuno-oncology; engineering antibodies for T-cell therapy; novel engineering strategies to enhance antibody functions; and the biological Impact of Fc receptor engagement. The meeting will open with keynote speakers Dennis R. Burton (The Scripps Research Institute), who will review progress toward a neutralizing antibody-based HIV vaccine; Olivera J. Finn, (University of Pittsburgh School of Medicine), who will discuss prophylactic cancer vaccines as a source of therapeutic antibodies; and Paul Richardson (Dana-Farber Cancer Institute), who will provide a clinical update on daratumumab for multiple myeloma. In a featured presentation, a representative of the World Health Organization's INN expert group will provide a perspective on antibody naming. “Antibodies to watch in 2017” and progress on The Antibody Society's 2016 initiatives will be presented during the Society's special session. In addition, two pre-conference workshops covering ways to accelerate antibody drugs to the clinic and the applications of next-generation sequencing in antibody discovery and engineering will be held on Sunday December 11, 2016

Molecular medicine and concepts of disease: the ethical value of a conceptual analysis of emerging biomedical technologies

Although it is now generally acknowledged that new biomedical technologies often produce new definitions and sometimes even new concepts of disease, this observation is rarely used in research that anticipates potential ethical issues in emerging technologies. This article argues that it is useful to start with an analysis of implied concepts of disease when anticipating ethical issues of biomedical technologies. It shows, moreover, that it is possible to do so at an early stage, i.e. when a technology is only just emerging. The specific case analysed here is that of ‘molecular medicine’. This group of emerging technologies combines a ‘cascade model’ of disease processes with a ‘personal pattern’ model of bodily functioning. Whereas the ethical implications of the first are partly familiar from earlier—albeit controversial—forms of preventive and predictive medicine, those of the second are quite novel and potentially far-reaching

C1q binding to surface-bound IgG is stabilized by C1r(2)s(2) proteases

Complement is an important effector mechanism for antibodymediated clearance of infections and tumor cells. Upon binding to target cells, the antibody's constant (Fc) domain recruits complement component C1 to initiate a proteolytic cascade that generates lytic pores and stimulates phagocytosis. The C1 complex (C1qr2s2) consists of the large recognition protein C1q and a heterotetramer of proteases C1r and C1s (C1r2s2). While interactions between C1 and IgG-Fc are believed to be mediated by the globular heads of C1q, we here find that C1r2s2 proteases affect the capacity of C1q to form an avid complex with surface-bound IgG molecules (on various 2,4-dinitrophenol [DNP]-coated surfaces and pathogenic Staphylococcus aureus). The extent to which C1r2s2 contributes to C1q-IgG stability strongly differs between human IgG subclasses. Using antibody engineering of monoclonal IgG, we reveal that hexamer-enhancing mutations improve C1q-IgG stability, both in the absence and presence of C1r2s2. In addition, hexamer-enhanced IgGs targeting S. aureus mediate improved complement-dependent phagocytosis by human neutrophils. Altogether, these molecular insights into complement binding to surface-bound IgGs could be important for optimal design of antibody therapies.Transplantation and autoimmunit