BACKGROUND:Detection of B cell clonality is useful for assisting in the diagnosis of B cell lymphomas. Clonality assessment can be accomplished through evaluation of KAPPA and LAMBDA light chain expression. Currently, only slide based methods are available for the majority of patient biopsies and do not detect light chain protein or mRNA in many B-cell lymphomas. Herein we evaluated a new method, known as colorimetric in situ hybridization (CISH), with improved sensitivity and multiplexing capacity, for its usefulness in clonality detection in mature B cell malignancies.METHODS:The KAPPA and LAMBDA ISH was performed on a Ventana Benchmark XT utilizing two color chromogenetic detection. The probes comprised 2 haptenated riboprobes each approximately 500 base pairs long directed against the conserved regions of either KAPPA or LAMBDA mRNA. The dual colors consisted of silver deposition (black) for KAPPA light chain and a novel (pink) chromogen for LAMBDA light chain. Following optimization, CISH allowed visualization of mRNA in benign B cells in reactive tissues including germinal center, mantle zone, and post-germinal center cells. We then identified 79 cases of B cell lymphoma with formalin-fixed paraffin-embedded (FFPE) biopsies including: follicular (36 cases), mantle cell (6 cases), marginal zone (12 cases), lymphoplasmacytic (6 cases), small lymphocytic (4 cases), and diffuse large B cell (15 cases), which were selected on the basis of either prior flow cytometry or immunohistochemistry (IHC) results to serve as the predicate, "gold standard," comparator.RESULTS:39/79 (49.4%) cases were classified as KAPPA and 29/79 (36.7%) as LAMBDA light chain restricted / while 9/79 (11.3%) cases were classified as indeterminate. Of the 70 cases with KAPPA or LAMBDA light chain restricted CISH, 69/70 (98.6%) were concordant with the reference method, while 1/70 (1.4%) was discordant.CONCLUSIONS:Optimized CISH detected lower levels of mRNA than can be visualized with current slide based methods, making clonality assessment in FFPE biopsies possible for mature B cell neoplasms. In this preliminary study, CISH was highly accurate compared to flow cytometry or IHC. CISH offers the possibility of wider applicability of light chain ISH and is likely to become a useful diagnostic tool.Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1430491067123856

Undersökningens syfte är att finna svar på vilka svårigheter elever i matematik kurs B har inom algebra samt undersöka vad svårigheterna beror på. Vi vill även undersöka hur elever går tillväga när de löser algebrauppgifter och särskilt belysa vilka fel eleverna gör. För att tydligt knyta an till målen i läroplanerna konstruerade vi ett algebratest med uppgifter från de nationella proven, vilket genomfördes i en teknikklass med 25 elever. Detta test tillsammans med semistrukturerade intervjuer med tre av eleverna och två lärare kring elevernas test utgjorde vår metod för datainsamling i denna kvalitativa studie. Resultatet visar att eleverna har stora svårigheter med flera olika delar inom algebra i matematik B, exempelvis ekvationssystem, kvadratkomplettering och förenkling av uttryck. Vårt resultat visar också att svårigheterna bland annat beror på att eleverna har brister i sina algebrakunskaper från grundskolan, de använder inte de metoder som lärarna visar och de övar inte tillräckligt.

International Telemetering Conference Proceedings / October 23-26, 2000 / Town & Country Hotel and Conference Center, San Diego, California / This paper will provide an overview of the process used to develop the bandwidth efficient modulation sections of the Inter-Range Instrumentation Group (IRIG) standard. The modulation method selected was Feher’s patented quadrature phase shift keying (FQPSK-B). The important characteristics of a bandwidth efficient modulation method for aeronautical telemetry will be presented first followed by a summary of the results of the research, laboratory test, and flight test efforts. Future plans will then be summarized followed by the FQPSK-B sections of the current IRIG Telemetry Standard (the standard is available online at: http://tecnet0.jcte.jcs.mil/RCC/oldoc.htm).

In this thesis I describe an investigation into the function of the protein Icb-1, a homologue of Themis1 in B cells and monocytes. Themis1 is important for T cell positive and negative selections. Yet its function in T cell development is not clear. Although it shows characteristics of an adaptor protein and involvement in TCR-induced signalling, the exact signalling defects in Themis1-/- T cells remain obscure. Icb-1 is similar to Themis1 in sequence, function and binding partners. It has been studied in human tumour and macrophage cell lines, leading to limited conclusions. Its role in B cells has never been published. Given the link with Themis1, it is of great interest to investigate the function of Icb-1. My study has been focused on the comparison between Icb-1 knockout mice with wild-type controls. I characterised the B cell development in Icb-1-/- mice, either naturally born or produced as mixed adult bone marrow chimeras reconstituted from WT and Icb-1-/- donor cells. I examined the possible compensation and redundancy of Themis1 and Icb-1, by characterising Thems1/Icb-1 double knockout mice. The Ig-HEL mouse models were used to examine the change in B cell repertoire due to negative and positive selections. The mice were challenged with SRBCs or NP-CGG to examine the germinal centre response to foreign antigen when Icb-1 is absent. In vitro stimulation of B cells with soluble and membrane-bound antigens was used to investigate early B cell responses in detail and to give insights into the defects found in in vivo challenges. Finally, I examined the BCR-induced phosphorylation of key signalling molecules and Ca2+ flux in splenic B cells. The study revealed largely normal B cell development with subtle selection impairments, but a partially defected B cell immune response to antigens in Icb-1-/- mice. The marginal zone B cell population was enlarged in the absence of Icb-1, while the positive selection of B1 B cells induced by intracellular self-antigen was impaired. The deficient mice showed a reduction in germinal centre B cell generation. The defects are associated with impaired BCR-induced cell signalling to low abundance and/or low avidity antigens. In particular, Ca2+ flux and Erk1/2 phosphorylation were clearly reduced under certain conditions. The results shine a light on the function of protein Icb-1, and also improve our knowledge of Themis1 and the Themis family. They provide a new avenue of investigation into the regulation of BCR signalling, especially in Ca2+ flux induction and Erk1/2 activation. They also provide insight into how differential signalling is controlled within cells during activation and differentiation in response to antigens that vary in terms of affinity, avidity and frequency.

This thesis traces the dynamic between labour and learning as it was figured by Scottish writers in the period 1759-1828. Vocational specialization and engagement with a literary field that traversed professional and disciplinary boundaries were the twin imperatives of the Scottish Enlightenment’s modernising credo. But the division of labour was also associated with a narrowing of intellectual and moral capacity thought to be incompatible with the exhortations of politeness and civility. Leisured cultivation offered readers and writers a middle ground in which to negotiate between these contradictory demands. This study explores the way in which this culture of intellectual improvement was claimed by authors and readers involved in manual labour as a counterinfluence to the rigours of work, and as a civilizing prerogative that extended to all social levels. But others registered significant anxiety towards the destabilising effects of excessive delicacy or refinement, and feared that these might be exacerbated by contact with the necessity of bodily labour. I argue that this contributed to a redressing of the content and purpose of popular education that sought to match it to the role of the lower classes within the economic and political order. Particular attention is paid in the following study to authors who either claimed or were ascribed a labouring identity such as Robert Burns and James Hogg, but I also deal with lesser-known writers, and frame their engagement with intellectual improvement through broader eighteenth-century discourses on the division of labour and the theory of mind. In doing so, I discuss a variety of genres and forms, including philosophical and economic treatises, poetry, memoir, biography, the novel, and the literary periodical.

The main research question of this thesis is: How can cross-border access to human genetic resources, such as blood or DNA samples, be governed to achieve equity for developing countries? Access to and benefit sharing for human biological resources is not regulated through an international legal framework such as the Convention on Biological Diversity, which applies only to plants, animals and micro-organisms as well as associated traditional knowledge. This legal vacuum for the governance of human genetic resources can be attributed (in part) to the concern that benefit sharing might provide undue inducements to research participants and their communities. This thesis shows that: (a) Benefit sharing is crucial to avoiding the exploitation of developing countries in genomic research. (b) With functioning research ethics committees, undue inducement is less of a concern in genetic research than in other medical research (e.g. clinical trials). (c) Concerns remain over research involving indigenous populations and some recommendations are provided. In drawing its conclusions, the thesis resolves a highly pressing topic in global bioethics and international law. Originally, it combines bioethical argument with jurisprudence, in particular reference to the law of equity and the legal concepts of duress (coercion), unconscionable dealing, and undue influence.

Recent European legislation has enforced a reduction in the use of animal models for safety assessment purposes and carcinogenicity testing. The Syrian hamster embryo cell transformation assay (SHE CTA) has been proposed as a suitable animal alternative, but its implementation into test batteries has been delayed. This is due to concerns regarding the assay’s endpoint subjectivity and, moreover, the model’s relevance to carcinogenicity remains mostly unexplored. Senescence is an essential barrier against uncontrolled cell proliferation and its evasion is necessary for clonal evolution and tumour development. Carcinogenesis can be modelled by reproducing underlying mechanisms leading to senescence bypass. In this project, the SHE CTA was performed using the known mutagen and human carcinogen, benzo(a)pyrene, and the resulting SHE colonies were analysed. It was found that morphological transformation (MT) does not guarantee senescence bypass and cell immortalisation, but increases the likelihood of MT-derived cells subsequently acquiring unlimited growth potential. A limited number (between 10 and 20 %) of MT colonies produced cell clones capable of sustained proliferation and in most cases secondary events were necessary for the evasion of senescence barriers. With regard to mechanisms, p53 point mutations were present in 30 % of immortal B(a)P-induced MT colony-derived cells and located within the protein’s DNA binding domain. No p16 mutations were identified. Expression of p16 mRNA was commonly silenced or markedly reduced by a combination of mechanisms including monoallelic deletion, promoter methylation and BMI-1 overexpression. Taking advantage of the recently available Syrian hamster genomic sequence information generated by the Broad Institute, the coding regions of the Syrian hamster CDKN2A/B locus were shown to have good homology to human nucleotide sequences and confirmed the exonic structures of SH p16, ARF and p15. The findings further implicate the importance of p16 in regulating senescence while providing a molecular evaluation of SHE CTA-derived MT clones.

The study of flavour physics allows for the Standard Model (SM) to be tested to higher energies than can be accessed through direct searches. The SM is known not to provide enough of a difference between matter and anti-matter, termed CP violation, to explain the dominance of matter in our universe. One of the main purposes of the LHCb experiment is to search for new sources of CP violation in the decays of B mesons. Flavour changing neutral current (FCNC) interactions are forbidden at tree level in the SM, and can therefore only be accessed through quantum loops. In New Physics scenarios such as Supersymmetry, new particles could appear in those loops introducing new sources of CP violation. The Bos→ØØ decay proceeds via the b → sss FCNC transition. Triple products provide a method of exploiting the angular distributions of P → V V decays to create T-odd observables. Asymmetries of these T-odd observables, averaged over the initial flavour of the Bos meson provide a measure of T violation. Assuming CPT conservation, violation of time reversal infers CP violation. The CP-violating weak phase in the interference between Bos mixing and the decay to two Ø mesons is predicted to be close to zero in the SM. The measurements of the triple product asymmetries and the CP-violating weak phase have been performed using 1.0 fb-1 of LHCb data. Events where kaon pairs originate from a spin-0 or non-resonant state are accounted for with the associated angular distributions. Triple product asymmetries are measured to be AU = -0:055 ± 0:036(stat) ± 0:018(syst) and Av = 0:010 ± 0:036(stat) ± 0:018(syst). The CP-violating phase is found to be in the interval [-2:46,-0:76] rad at 68% confidence level. The p-value for the hypothesis of zero radians is found to be 16 %. These results represent the most accurate measurements of the triple product asymmetries and the first measurement of the CP-violating weak phase.

International Telemetering Conference Proceedings / October 26-29, 1998 / Town & Country Resort Hotel and Convention Center, San Diego, California / Instrumenting the operational B-2 Strategic Bomber presents some unique problems. For example, the requirement to remain operational dictates that the aircraft must retain its stealth characteristics. This means traditional antennas cannot simply be attached to the airframe. A solution to this problem is an antenna designed with stealth, or Low Observable (LO), attributes. Stealth is not an absolute; it is relative. Therefore, antenna design becomes a balancing act between the LO relativity, antenna directivity, and antenna gain. Weapons testing is an additional concern, where instrumented ordinances transmit data that must be monitored real-time prior to launch. Stealth vehicles must carry weapons internally, restricting the Radio Frequency (RF) transmission of telemetered data from the weapon. With the development of future stealthy conveyances, such as the F-22, Joint Strike Fighter (JSF), ground, and ocean-going craft, these concerns will become even more prevalent.

International Telemetering Conference Proceedings / October 21, 2002 / Town & Country Hotel and Conference Center, San Diego, California / Designers of small airborne FQPSK-B (-B) transmitters face at least two significant challenges. First, many U.S. Department of Defense (DOD) test applications require that transmitters accommodate a continuum of data rates from 1, to at least 20 Mb/s in one design. Another challenge stems from the need to package a high-speed digital baseband signal generator in very close proximity to radio frequency (RF) circuitry required for 1.4 to 2.4 GHz operation. The -B baseband filter options prescribed by Digcom/Feher [2] are a major contributor to variable data rate design challenges. This paper summarizes a study of -B filter alternatives and introduces FQPSK-JR (JR), an alternative to -B that can simplify digital baseband transmitter designs. Very short impulse response digital filters are used to produce essentially the same spectral efficiency and nonlinear amplifier (NLA) compatibility as -B while preserving or improving detection efficiency (DE). In addition, a strategy for eliminating baseband shaping filters is briefly discussed. New signaling wavelets and, modified wavelet versus symbol sequence mapping rules associated with them, can be captured from a wide range of alternative filter designs.