Immune defects in Alzheimer's disease: new medications development

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of intracellular and extracellular aggregates. According to the amyloid beta (Aβ) hypothesis, amyloidosis occurring in the brain is a leading cause of neurodegeneration in AD. Defects in the innate immune system may decrease the clearance of Aβ in the brain. Macrophages of most AD patients do not transport Aβ into endosomes and lysosomes, and monocytes from AD patients do not efficiently clear Aβ from AD brain. After stimulation with Aβ, mononuclear cells of normal subjects display up-regulated transcription of MGAT3, which encodes β-1,4-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase, and Toll-like receptor (TLR) genes. Monocytes of AD patients generally down-regulate these genes. A commonly used, naturally occurring material from a spice that enhances certain key functions defective in cells of innate immunity of many AD patients has shown epidemiologic rationale for use in AD treatment. Bisdemethoxycurcumin, a natural curcumin, is a minor constituent of turmeric (curry), and it enhances phagocytosis and clearance of Aβ in cells from most AD patients. We confirmed the effectiveness of a synthetic version of the same compound. In mononuclear cells of most AD patients, bisdemethoxycurcumin enhanced defective phagocytosis of Aβ and increased the transcription of MGAT3 and TLR genes. The potency of bisdemethoxycurcumin as a highly purified compound in facilitating the clearance of Aβ in mononuclear cells suggests the promise of enhanced effectiveness compared to curcuminoid mixtures. Bisdemethoxycurcumin appears to enhance immune function in mononuclear cells of AD patients and may provide a novel approach to AD immunotherapy

Amyotrophic Lateral Sclerosis: Proteins, Proteostasis, Prions, and Promises

Copyright 2020 McAlary, Chew, Lum, Geraghty, Yerbury and Cashman. Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of the motor neurons that innervate muscle, resulting in gradual paralysis and culminating in the inability to breathe or swallow. This neuronal degeneration occurs in a spatiotemporal manner from a point of onset in the central nervous system (CNS), suggesting that there is a molecule that spreads from cell-to-cell. There is strong evidence that the onset and progression of ALS pathology is a consequence of protein misfolding and aggregation. In line with this, a hallmark pathology of ALS is protein deposition and inclusion formation within motor neurons and surrounding glia of the proteins TAR DNA-binding protein 43, superoxide dismutase-1, or fused in sarcoma. Collectively, the observed protein aggregation, in conjunction with the spatiotemporal spread of symptoms, strongly suggests a prion-like propagation of protein aggregation occurs in ALS. In this review, we discuss the role of protein aggregation in ALS concerning protein homeostasis (proteostasis) mechanisms and prion-like propagation. Furthermore, we examine the experimental models used to investigate these processes, including in vitro assays, cultured cells, invertebrate models, and murine models. Finally, we evaluate the therapeutics that may best prevent the onset or spread of pathology in ALS and discuss what lies on the horizon for treating this currently incurable disease

Autoethnographic and qualitative research on popular music: Exploring the blues, jazz, grime, John Cage, live performance, SoundCloud and the masculinities of metal

This special edition of Riffs focuses on autoethnography and qualitative research in relation to popular music. The journal publication is twinned with a forthcoming book entitled: Popular Music Ethnographies: practice, place, identity. The intention of these studies is to uphold the principle that ‘music is good to think with’ (Chambers 1981: 38). Riffs was founded in 2015 to promote experimental writing on popular music, with a strong DiY ethos and space to offer flexibility and diversity of outputs through challenging interdisciplinary boundaries. At the same time there is a degree of similarity with specialist popular music magazines including Mojo, fRoots (1979-2019), Rolling Stone, Record Collector, Prog, Mixmag, and Uncut, through a focus on visuals and creative images. This suggests that there has been an increased growth at the ‘popular’ end of biographical and autoethnography within popular music. Critically, popular music autoethnographies work across and within disciplinary boundaries of anthropology, social anthropology, cultural studies, sociology, and popular music studies

Sports mega-events – three sites of contemporary political contestation

This article discusses the contemporary politics of sports mega-events, involving the Olympic Games and Fédération Internationale de Football Association (FIFA) Men’s Football World Cup Finals as well as other lower ‘order’ sports megas, taking two main forms: the promotional and the protest. There is a politics in, and a politics of, sports mega-events. The former focuses on the internal politics of the organizing bodies, such as the International Olympic Committee and FIFA. This form of politics has been written about elsewhere, and hence, there is no detailed discussion in this article about it. Instead this article offers a brief discussion of the range and number of sports mega-events since 2000, an assessment of the contemporary politics of sports mega-events, a focus on three main sites of political contestation – rights, legacy and labour, and finally, it offers conclusions about research into the politics of sports mega-events

Diet and bone mineral density study in postmenopausal women from the TwinsUK registry shows a negative association with a traditional English dietary pattern and a positive association with wine

Background: The effect of diet on bone mineral density (BMD) remains controversial, mainly because of difficulties in isolating dietary factors from the confounding influences of age, lifestyle, and genetic factors. Objective: The aim of this study was to use a novel method to examine the relation between BMD and diet. Design: A co-twin control study design with linear regression modeling was used to test for associations between BMD and habitual intakes of calcium, vitamin D, protein, and alcohol plus 5 previously identified dietary patterns in postmenopausal women from the TwinsUK registry. This approach exploited the unique matching of twins to provide an estimate of an association that was not confounded by age, genetic background, or shared lifestyle. Results: In >2000 postmenopausal women (BMD data on 1019, 1218, and 1232 twin pairs at the hip neck, hip, and spine, respectively), we observed a positive association between alcohol intake (from wine but not from beer or spirits) and spine BMD (P = 0.01) and a negative association with a traditional 20th-century English diet at the hip neck (P = 0.01). Both associations remained borderline significant after adjustment for mean twin-pair intakes (P = 0.04 and P = 0.055, respectively). Other dietary patterns and intakes of calcium, vitamin D, and protein were unrelated to BMD. Conclusion: Our results showed that diet has an independent but subtle effect on BMD; wine intake was positively associated with spine BMD, whereas a traditional (20th-century) English diet had a negative association with hip BMD

Transient trimethylaminuria related to menstruation

BACKGROUND: Trimethylaminuria, or fish odor syndrome, includes a transient or mild malodor caused by an excessive amount of malodorous trimethylamine as a result of body secretions. Herein, we describe data to support the proposal that menses can be an additional factor causing transient trimethylaminuria in self-reported subjects suffering from malodor and even in healthy women harboring functionally active flavin-containing monooxygenase 3 (FMO3). METHODS: FMO3 metabolic capacity (conversion of trimethylamine to trimethylamine N-oxide) was defined as the urinary ratio of trimethylamine N-oxide to total trimethylamine. RESULTS: Self-reported Case (A) that was homozygous for inactive Arg500stop FMO3, showed decreased metabolic capacity of FMO3 (i.e., ~10% the unaffected metabolic capacity) during 120 days of observation. For Case (B) that was homozygous for common [Glu158Lys; Glu308Gly] FMO3 polymorphisms, metabolic capacity of FMO3 was almost ~90%, except for a few days surrounding menstruation showing < 40% metabolic capacity. In comparison, three healthy control subjects that harbored heterozygous polymorphisms for [Glu158Lys; Glu308Gly] FMO3 or homozygous for wild FMO3 showed normal (> 90%) metabolic capacity, however, on days around menstruation the FMO3 metabolic capacity was decreased to ~60–70%. CONCLUSION: Together, these results indicate that abnormal FMO3 capacity is caused by menstruation particularly in the presence, in homozygous form, of mild genetic variants such as [Glu158Lys; Glu308Gly] that cause a reduced FMO3 function