John Philip Sousa and the Wagner Overture: A New Transcription of the Overture to Der fliegende Holländer for Wind Orchestra

This research examines John Philip Sousa’s 1893 wind band transcription of Richard Wagner’s overture to Der fliegende Holländer, and focuses specifically on how Sousa reconceived orchestral sonorities and solved particular problems posed by Wagner’s complex orchestrational textures. Findings include that, while appropriate for the era and instrumentation of Sousa’s band, his transcription contains certain limitations for the twenty-first-century wind orchestra. Due to the fact that Sousa’s compositions, arrangements, and transcriptions were written to accommodate frequent outdoor performances, Sousa’s transcription uses more doubled voicings than would be necessary in an indoor concert hall setting. Further, while Sousa’s instrumentation approximates that of the modern wind orchestra, there are notable differences that must be resolved. For these reasons, an update to Sousa’s transcription is needed. As a culminating product of this research, I am including my transcription for wind orchestra of Wagner’s overture to Der fliegende Holländer. In this transcription, I have taken great care to maintain the spirit of Sousa’s while bringing more relevance to the concert hall wind orchestra approach popular in the twenty- first century. I have restored the overture to its original key; maintained the original wind, brass, and timpani parts of Wagner’s orchestral score; and, as often as possible, eliminated doubling of voices unnecessary in the concert hall. I have also updated the instrumentation to today’s needs and added a cello, double bass, and a full complement of harmony clarinets to accentuate a sonic landscape that uses the various colors and timbre possibilities of the modern wind orchestra

Discrimination between CMV infection and Alzheimer's disease as driving forces for immune senescence

This study investigated the immune profiles of patients with dementia. The focus of this study was on leukocyte populations found in the blood. Initial experiments assessed the frequency of major leukocyte subsets in AD patients and healthy controls, but no differences were observed - the frequencies of B-cells, NK-cells and NKT-like cells were similar for all groups. The monocyte marker CD14 tended to be less frequently expressed in control subjects compared to AD patients, but the results differed across the cohorts that were studied. In the second phase of this study, the phenotype of different leukocyte populations was analysed. B-cells showed a tendency towards a lowered frequency of CD27-IgD+ naïve cells in AD patients compared to healthy controls. This trend was even more pronounced for T-cells, notably in the case of CD4+ T-cells. The frequencies of Naïve CD4+ T-cells were lower in AD patients than in controls in pilot studies as well as larger cohorts. Parallel to this, the percentages of late-differentiated CD4+ T-cells were found elevated in AD patients. In addition, the frequency of CD57- and KLRG-positive cells tended to be greater in patients than controls, but these differences were only statistically significant in some cohorts. Another observation, indicative of immune exhaustion, was an increased level of PD-1 in T-cells of AD patients compared with controls, although this was also not statistically significant. The question remains, which is the factor causing these immune changes in AD. One possible explanation is that Aβ is causing chronic antigenic stress and driving T-cell differentiation. Further studies investigated chemokine receptor expression. In AD, a compromised and potentially leaky blood-brain barrier results in an exchange between the periphery and the brain that does usually not occur. A consequence is that cytokines, Aβ protein and cells may migrate through the BBB contributing to systemic inflammation. One aspect of AD pathology is the potential recruitment of immune cells to the brain. To elucidate the mechanisms behind these processes, the frequency of peripheral leukocytes expressing CCR2, CCR4, CCR5 and CCR6 was determined. The results indicated that leukocytes from AD patients more frequently expressed these proteins, although the differences were not always statistically significant in all cohorts. In the case of CCR6, it was observed that this receptor was not only more often expressed on a single leukocyte subset, but expressed more frequently on B-cells, monocytes, CD4+ and CD8+ T-cells as well. In conclusion, this work provides evidence that hints toward a more differentiated and exhausted immune system in AD patients. What still remains unclear is whether the recruitment of immune cells to the brain is a consequence or cause of the disease. Experiments using in vitro models where the entry of immune cells to the brain can be blocked may provide insight into this lingering question. These experiments may also assist in determining if the migration of immune cells results in beneficial effects, for example by phagocytosing Aβ protein, or if they function to promote disease progression assuming that in vitro models accurately parallel human disease. A way of investigating this could be to enhance the chemokine gradient in vivo, as the immune cells examined in this study demonstrated increased CCR expression. In the event that immune cells are found to promote AD, it may be possible to treat patients with CCR-blockers in order to reduce immune cell migration to the brain. Using this approach, it may be possible to selectively block B-cell migration as they were observed to express CCR6, but not CCR4 or CCR5. After determining which leukocyte subset contributes to the promotion of disease, it may be possible to employ antibodies specific to CCRs that are predominately expressed on this subset. It is hypothesised that a rejuvenation of the immune system may be beneficial for AD patients. This might be achieved through improving Aβ clearance, possibly by enhancing monocyte migration from the periphery to the brain. Reduced Aβ load may result in reduced T-cell differentiation, i.e. fewer memory T-cells and more naïve T-cells. It is thought that in AD patients as in healthy elderly CMV is the driving force of CD8+ T-cell differentiation and Aβ may have a similar effect. Whether the effects of CMV and Aβ are additive remains to be determined. A larger cohort of study participants - as recruited here - including sufficient CMV- and CMV+ AD patients and controls would be necessary to investigate this. This question may be of particular importance given that CMV may contribute to inflammation in AD and thus provide another burden to the functioning of the immune system thereby decreasing the ability of the body to control the disease. The role that CMV may play in the functional decline of the immune system may also be related to cognitive decline, such as that in AD

Apollo: A System for Tracking Internet Censorship

If it remains debatable whether the Internet has surpassed print media in making information accessible to the public, then it must nevertheless be conceded that the Internet makes the manipulation and censorship of information easier than had been on the printed page. In coming years and in an increasing number of countries, everyday producers and consumers of online information will likely have to cultivate a sense of censorship. It behooves the online community to learn how to detect and evade interference by governments, regimes, corporations, con-artists, and vandals. The contribution of this research is to describe a method and platform to study Internet censorship detection and evasion. This paper presents the concepts, initial theories, and future work

Higher Lipoprotein (a) Levels Are Associated with Better Pulmonary Function in Community-Dwelling Older People - Data from the Berlin Aging Study II

Reduced pulmonary function and elevated serum cholesterol levels are recognized risk factors for cardiovascular disease. Currently, there is some controversy concerning relationships between cholesterol, LDL-cholesterol, HDL-cholesterol, serum triglycerides and lung function. However, most previous studies compared patients suffering from chronic obstructive pulmonary disease (COPD) with healthy controls, and only a small number examined this relationship in population-based cohorts. Moreover, lipoprotein a [Lp(a)], another lipid parameter independently associated with cardiovascular diseases, appears not to have been addressed at all in studies of lung function at the population level. Here, we determined relationships between lung function and several lipid parameters including Lp(a) in 606 older community-dwelling participants (55.1% women, 68±4 years old) from the Berlin Aging Study II (BASE-II). We found a significantly lower forced expiration volume in 1 second (FEV1) in men with low Lp(a) concentrations (t-test). This finding was further substantiated by linear regression models adjusting for known covariates, showing that these associations are statistically significant in both men and women. According to the highest adjusted model, men and women with Lp(a) levels below the 20th percentile had 217.3ml and 124.2ml less FEV1 and 239.0ml and 135.2ml less FVC, respectively, compared to participants with higher Lp(a) levels. The adjusted models also suggest that the known strong correlation between pro-inflammatory parameters and lung function has only a marginal impact on the Lp(a)-pulmonary function association. Our results do not support the hypothesis that higher Lp(a) levels are responsible for the increased CVD risk in people with reduced lung function, at least not in the group of community-dwelling older people studied here

Functional Changes of T-Cell Subsets with Age and CMV Infection

Cytomegalovirus (CMV) latent infection and aging contribute to alterations in the function and phenotype of the T-cell pool. We have demonstrated that CMV-seropositivity is associated with the expansion of polyfunctional CD57+ T-cells in young and middle-aged individuals in response to different stimuli. Here, we expand our results on the effects of age and CMV infection on T-cell functionality in a cohort of healthy middle-aged and older individuals stratified by CMV serostatus. Specifically, we studied the polyfunctional responses (degranulation, IFN-γ and TNF-α production) of CD4+, CD8+, CD8+CD56+ (NKT-like), and CD4-CD8- (DN) T-cells according to CD57 expression in response to Staphylococcal Enterotoxin B (SEB). Our results show that CD57 expression by T-cells is not only a hallmark of CMV infection in young individuals but also at older ages. CD57+ T-cells are more polyfunctional than CD57− T-cells regardless of age. CMV-seronegative individuals have no or a very low percentages of cytotoxic CD4+ T-cells (CD1017a+) and CD4+CD57+ T-cells, supporting the notion that the expansion of these T-cells only occurs in the context of CMV infection. There was a functional shift in T-cells associated with CMV seropositivity, except in the NKT-like subset. Here, we show that the effect of CMV infection and age differ among T-cell subsets and that CMV is the major driving force for the expansion of highly polyfunctional CD57+ T-cells, emphasizing the necessity of considering CMV serology in any study of immunosenescence

A novel B cell population revealed by a CD38/CD24 gating strategy: CD38(-)CD24 (-) B cells in centenarian offspring and elderly people

The B cell arm of adaptive immunity undergoes significant modifications with age. Elderly people are characterized by impaired B cell responses reflected in a reduced ability to effectively respond against viruses and bacteria. Alterations of immunity with advancing age (immunosenescence) have been widely studied in centenarians who are considered a good example of successful aging. In recent years, attention has shifted to centenarian offspring (CO) as a model of people genetically advantaged for healthy aging and longevity. Here, we describe the preliminary characterization of a proposed new population of memory B cells, defined as CD19(+)CD38(-)CD24(-), which we find at higher frequencies in the elderly but less so in CO than healthy age-matched random controls. In addition, we found a decreased expression of RP105 (CD180), a toll-like receptor-associated molecule, on these cells. CD180 downregulation may potentially be a marker of immunosenescence. Moreover, we show that these CD19(+)CD38(-)CD24(-) B cells produce TNF and hypothesize that their observed expansion in the elderly might contribute to the increased inflammatory status sometimes designated "inflamm-aging

Evidence for less marked potential signs of T-cell immunosenescence in centenarian offspring than in the general age-matched population

People may reach the upper limits of the human life span at least partly because they have maintained more appropriate immune function, avoiding changes to immunity termed "immunosenescence." Exceptionally long-lived people may be enriched for genes that contribute to their longevity, some of which may bear on immune function. Centenarian offspring would be expected to inherit some of these, which might be reflected in their resistance to immunosenescence, and contribute to their potential longevity. We have tested this hypothesis by comparing centenarian offspring with age-matched controls. We report differences in the numbers and proportions of both CD4(+) and CD8(+) early- and late-differentiated T cells, as well as potentially senescent CD8(+) T cells, suggesting that the adaptive T-cell arm of the immune system is more "youthful" in centenarian offspring than controls. This might reflect a superior ability to mount effective responses against newly encountered antigens and thus contribute to better protection against infection and to greater longevity

Immune profiling of Alzheimer patients

Alzheimer's disease (AD) is characterized by extracellular senile plaques in the brain, containing amyloid-β peptide (Aβ). We identify immunological differences between AD patients and age-matched controls greater than those related to age itself. The biggest differences were in the CD4+ rather than the CD8+ T cell compartment resulting in lower proportions of naïve cells, more late-differentiated cells and higher percentages of activated CD4+CD25+ T cells without a Treg phenotype in AD patients. Changes to CD4+ cells might be the result of chronic stimulation by Aβ present in the blood. These findings have implications for diagnosis and understanding the aetiology of the diseas

ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA

The cytosolic antiviral innate immune sensor RIG-I distinguishes 5' tri- or diphosphate containing viral double-stranded (ds) RNA from self-RNA by an incompletely understood mechanism that involves ATP hydrolysis by RIG-I's RNA translocase domain. Recently discovered mutations in ATPase motifs can lead to the multi-system disorder Singleton-Merten Syndrome (SMS) and increased interferon levels, suggesting misregulated signaling by RIG-I. Here we report that SMS mutations phenocopy a mutation that allows ATP binding but prevents hydrolysis. ATPase deficient RIG-I constitutively signals through endogenous RNA and co-purifies with self-RNA even from virus infected cells. Biochemical studies and cryo-electron microscopy identify a 60S ribosomal expansion segment as a dominant self-RNA that is stably bound by ATPase deficient RIG-I. ATP hydrolysis displaces wild-type RIG-I from this self-RNA but not from 5' triphosphate dsRNA. Our results indicate that ATP-hydrolysis prevents recognition of self-RNA and suggest that SMS mutations lead to unintentional signaling through prolonged RNA binding

ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA

The cytosolic antiviral innate immune sensor RIG-I distinguishes 5' tri- or diphosphate containing viral double-stranded (ds) RNA from self-RNA by an incompletely understood mechanism that involves ATP hydrolysis by RIG-I's RNA translocase domain. Recently discovered mutations in ATPase motifs can lead to the multi-system disorder Singleton-Merten Syndrome (SMS) and increased interferon levels, suggesting misregulated signaling by RIG-I. Here we report that SMS mutations phenocopy a mutation that allows ATP binding but prevents hydrolysis. ATPase deficient RIG-I constitutively signals through endogenous RNA and co-purifies with self-RNA even from virus infected cells. Biochemical studies and cryo-electron microscopy identify a 60S ribosomal expansion segment as a dominant self-RNA that is stably bound by ATPase deficient RIG-I. ATP hydrolysis displaces wild-type RIG-I from this self-RNA but not from 5' triphosphate dsRNA. Our results indicate that ATP-hydrolysis prevents recognition of self-RNA and suggest that SMS mutations lead to unintentional signaling through prolonged RNA binding