Treg and Oligoclonal Expansion of Terminal Effector CD8+ T Cell as Key Players in Multiple Myeloma

The classical paradigm of host-tumor interaction, i.e. elimination, equilibrium, and escape (EEE), is reflected in the clinical behavior of myeloma which progresses from the premalignant condition, Monoclonal Gammopathy of Unknown Significance (MGUS). Despite the role of other immune cells, CD4+ regulatory T cells (Treg) and cytotoxic CD8+ T cells have emerged as the dominant effectors of host control of the myeloma clone. Progression from MGUS to myeloma is associated with alterations in Tregs and terminal effector CD8+ T cells (TTE). These changes involve CD39 and CD69 expression, affecting the adenosine pathway and residency in the bone marrow (BM) microenvironment, together with oligoclonal expansion within CD8+ TTE cells. In this mini-review article, in the context of earlier data, we summarize our recent understanding of Treg involvement in the adenosine pathway, the significance of oligoclonal expansion within CD8+ TTE cells and BM-residency of CD8+ TTE cells in MGUS and newly diagnosed multiple myeloma patients

Family imaginaries in the disclosure of a blood-borne virus

Contemporary sociological work has emphasised that family is not static, but actively shaped by ideas of who and what makes family. Disclosure of an illness, including diagnosis of stigmatised infections such as HIV, hepatitis B virus and hepatitis C virus, can change the dynamics of family relationships. This paper draws on 61 qualitative semi-structured interviews conducted between 2017 and 2019 with people in Australia with one or more of these blood-borne viruses (BBVs) and their family members, to understand the experiences of serodiscordant (mixed viral status) families. Through a thematic analysis, we explore the family imaginaries that participants evoked when describing their disclosure practices in relation to (self-defined) family members, revealing how some participants disclosed in ways that enabled them to shape their family, to maintain boundaries between self and family or to protect family from distress. Participants' accounts of disclosure to family revealed imaginaries of family as a precious web of connections to be nurtured or protected, but also as sites of ambivalent belonging and complex history. We conclude that BBV disclosure practices within families reveal important ideas about families that are imagined in response to the threat of loss, change and stigma

Aboriginal peoples' perspectives about COVID-19 vaccines and motivations to seek vaccination: a qualitative study

Introduction Aboriginal and Torres Strait Islander (Aboriginal) people compared with non-Aboriginal people in Australia have higher rates of chronic conditions. These conditions increase the risk of poorer health outcomes if infected with COVID-19, highlighting the importance of COVID-19 vaccination. This study examined what Aboriginal people think about COVID-19 vaccines, reasons why they were vaccinated or not vaccinated and factors involved in receiving COVID-19 vaccination. Methods We used a participatory peer researcher method to interview 35 Aboriginal people aged 15-80 years living in Western Sydney, Australia. Local Aboriginal people who had ties with the community conducted the interviews. The questions and analyses were framed using the WHO's Behavioural and Social Drivers of COVID-19 model. Interviews occurred between February 2021 and March 2021. Peer researchers were paid for their time in training and to conduct the interviews and each participant received $50. Results Reasons why participants would seek vaccination included: to protect themselves from infection and severe illness, to protect others in their community, to travel again and to return to normal life'. Reasons why some participants were hesitant about being vaccinated included: fear of vaccine side effects; negative stories on social media; and distrust in Australian governments and medical institutions. Aboriginal people preferred to access COVID-19 vaccination through their local Aboriginal Health Service or a general practitioner they already knew. Conclusion Achieving high vaccination rates in Aboriginal communities is possible if vaccination programmes are delivered through trusted general practitioners or Aboriginal Health Services

Introducing EMMIE: An evidence rating scale to encourage mixed-method crime prevention synthesis reviews

Objectives This short report describes the need for, and the development of, a coding system to distil the quality and coverage of systematic reviews of the evidence relating to crime prevention interventions. The starting point for the coding system concerns the evidence needs of policymakers and practitioners. Methods The coding scheme (EMMIE) proposed builds on previous scales that have been developed to assess the probity, coverage and utility of evidence both in health and criminal justice. It also draws on the principles of realist synthesis and review. Results The proposed EMMIE scale identifies five dimensions to which systematic reviews intended to inform crime prevention should speak. These are the Effect of intervention, the identification of the causal Mechanism(s) through which interventions are intended to work, the factors that Moderate their impact, the articulation of practical Implementation issues, and the Economic costs of intervention

Cellulolytic Bacteria in the foregut of the dromedary camel (Camelus dromedarius)

Foregut digesta from five feral dromedary camels were inoculated into three different enrichment media: cotton thread, filter paper, and neutral detergent fiber. A total of 283 16S rRNA gene sequences were assigned to 33 operational taxonomic units by using 99% species-level identity. LIBSHUFF revealed significant differences in the community composition across all three libraries

Differential Dynamics of Transposable Elements during Long-Term Diploidization of Nicotiana Section Repandae (Solanaceae) Allopolyploid Genomes

PubMed ID: 23185607This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The N-terminal loop of IRAK-4 death domain regulates ordered assembly of the Myddosome signalling scaffold

Activation of Toll-like receptors induces dimerization and the recruitment of the death domain (DD) adaptor protein MyD88 into an oligomeric post receptor complex termed the Myddosome. The Myddosome is a hub for inflammatory and oncogenic signaling and has a hierarchical arrangement with 6-8 MyD88 molecules assembling with exactly 4 of IRAK-4 and 4 of IRAK-2. Here we show that a conserved motif in IRAK-4 (Ser8-X-X-X-Arg12) is autophosphorylated and that the phosphorylated DD is unable to form Myddosomes. Furthermore a mutant DD with the phospho-mimetic residue Asp at this position is impaired in both signalling and Myddosome assembly. IRAK-4 Arg12 is also essential for Myddosome assembly and signalling and we propose that phosphorylated Ser8 induces the N-terminal loop to fold into an α-helix. This conformer is stabilised by an electrostatic interaction between phospho-Ser8 and Arg12 and would destabilise a critical interface between IRAK-4 and MyD88. Interestingly IRAK-2 does not conserve this motif and has an alternative interface in the Myddosome that requires Arg67, a residue conserved in paralogues, IRAK-1 and 3(M).This work was supported by program grants from the Wellcome Trust (WT081744/Z/06/Z) and the UK Medical Research Council (G1000133) to N.J.G. and C.E.B. and a Wellcome Investigator award to N.J.G. (WT100321/z/12/Z). AD was the recipient of a studentship award from GlaxoSmithKline. JG was supported by the German Cancer Research Center (DKFZ). ANRW was supported by the Else-Kröner-Fresenius-Stiftung, the German Research Foundation (Grant SFB685 “Immunotherapy”) and the University of Tübingen. PGM was supported by a Thuthuka Grant from the S. African NRF (TTK14060668443)

Nanobodies raised against monomeric alpha-synuclein inhibit fibril formation and destabilize toxic oligomeric species

BACKGROUND: The aggregation of the protein ɑ-synuclein (ɑS) underlies a range of increasingly common neurodegenerative disorders including Parkinson’s disease. One widely explored therapeutic strategy for these conditions is the use of antibodies to target aggregated ɑS, although a detailed molecular-level mechanism of the action of such species remains elusive. Here, we characterize ɑS aggregation in vitro in the presence of two ɑS-specific single-domain antibodies (nanobodies), NbSyn2 and NbSyn87, which bind to the highly accessible C-terminal region of ɑS. RESULTS: We show that both nanobodies inhibit the formation of ɑS fibrils. Furthermore, using single-molecule fluorescence techniques, we demonstrate that nanobody binding promotes a rapid conformational conversion from more stable oligomers to less stable oligomers of ɑS, leading to a dramatic reduction in oligomer-induced cellular toxicity. CONCLUSIONS: The results indicate a novel mechanism by which diseases associated with protein aggregation can be inhibited, and suggest that NbSyn2 and NbSyn87 could have significant therapeutic potential

Aboriginal young people’s perspectives and experiences of accessing sexual health services and sex education in Australia: A qualitative study

Aboriginal and Torres Strait Islander (Aboriginal) young people seek information and access health services for their sexual health needs. This study examined Aboriginal young people’s perspectives on sexual health services and sex education in Australia. Overall, 51 Aboriginal people aged 16–26 years were interviewed by peer researchers in Sydney, Australia in 2019–2020. The findings suggest that the internet was used to assess information quickly and confidentially, but Aboriginal young people questioned its reliability and accuracy. Family, Elders and peers were seen as sources of advice because they had real-life experience and highlighted intergenerational learning that occurs in Aboriginal communities. School-based sex education programmes had mixed reviews, with a preference for programmes delivered by external specialists providing anonymity, clear and accurate information about sex and relationships and positive approaches to sex education, including how to gain consent before sex. There was a need identified for school-based programmes to better consider the needs of Aboriginal young people, including those who identified as LGBTQI +. Aboriginal Medical Services were highly valued for providing culturally safe access to services, while sexual health clinics were valued for providing specialised confidential clinical services with low levels of judgement