Identification of pannexin 1-regulated genes, interactome, and pathways in rhabdomyosarcoma and its tumor inhibitory interaction with AHNAK

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, is an aggressive cancer with a poor prognosis. Despite current management, the 5-year survival rate for patients with metastatic RMS is ∼30%; underscoring the need to develop better treatment strategies. We have recently reported that pannexin 1 (PANX1) levels are downregulated in RMS and that restoring its expression inhibits RMS progression. Here, we have surveyed and characterized the molecular changes induced by PANX1 re-expression in RMS. We cataloged transcriptomic changes in this context by RNA sequencing. At the protein level, we unveiled PANX1 interactors using BioID, complemented by co-immunoprecipitation coupled to high-performance liquid chromatography/electrospray ionization tandem mass spectrometry performed in PANX1-enriched fractions. Using these data, we generated searchable public databases for the PANX1 interactome and changes to the RMS transcriptome occurring when PANX1 expression is restored. STRING network analyses revealed a PANX1 interactome involving plasma membrane and cytoskeleton-associated proteins including the previously undescribed interactor AHNAK. Indeed, AHNAK knockdown abrogated the PANX1-mediated reduction in RMS cell viability and migration. Using these unbiased approaches, we bring insight to the mechanisms by which PANX1 inhibits RMS progression, identifying the cell migration protein AHNAK as a key modifier of PANX1-mediated changes in RMS malignant properties

Identification of pannexin 1-regulated genes, interactome, and pathways in rhabdomyosarcoma and its tumor inhibitory interaction with AHNAK

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, is an aggressive cancer with a poor prognosis. Despite current management, the 5-year survival rate for patients with metastatic RMS is ∼30%; underscoring the need to develop better treatment strategies. We have recently reported that pannexin 1 (PANX1) levels are downregulated in RMS and that restoring its expression inhibits RMS progression. Here, we have surveyed and characterized the molecular changes induced by PANX1 re-expression in RMS. We cataloged transcriptomic changes in this context by RNA sequencing. At the protein level, we unveiled PANX1 interactors using BioID, complemented by co-immunoprecipitation coupled to high-performance liquid chromatography/electrospray ionization tandem mass spectrometry performed in PANX1-enriched fractions. Using these data, we generated searchable public databases for the PANX1 interactome and changes to the RMS transcriptome occurring when PANX1 expression is restored. STRING network analyses revealed a PANX1 interactome involving plasma membrane and cytoskeleton-associated proteins including the previously undescribed interactor AHNAK. Indeed, AHNAK knockdown abrogated the PANX1-mediated reduction in RMS cell viability and migration. Using these unbiased approaches, we bring insight to the mechanisms by which PANX1 inhibits RMS progression, identifying the cell migration protein AHNAK as a key modifier of PANX1-mediated changes in RMS malignant properties

ParaMED Home: A protocol for a randomised controlled trial of paramedic assessment and referral to access medical care at home

<p>Abstract</p> <p>Background</p> <p>In Australia approximately 25% of Emergency Department (ED) attendances are via ambulance. ED overcrowding in Australia, as in many countries, is common. Measures to reduce overcrowding include the provision of enhanced timely primary care in the community for appropriate low risk injury and illness. Therefore paramedic assessment and referral to a community home hospital service, in preference to transfer to ED, may confer clinical and cost benefit.</p> <p>Methods/Design</p> <p>A randomised controlled trial. Consenting adult patients that call an ambulance and are assessed by paramedics as having an eligible low risk problem will be randomised to referral to ED via ambulance transfer or referral to a rapid response service that will assess and treat the patient in their own residence. The primary outcome measure is requirement for unplanned medical attention (in or out of hospital) in the first 48 hours. Secondary outcomes will include a number of other clinical endpoints. A cost effectiveness analysis will be conducted.</p> <p>Discussion</p> <p>If this trial demonstrates clinical non-inferiority and cost savings associated with the primary assessment service, it will provide one means to safely address ED overcrowding.</p> <p>Trial Registration</p> <p>Australian and New Zealand Clinical Trials Registry Number <a href="http://www.anzctr.org.au/trial_view.aspx?ID=335818">12610001064099</a></p

A Mi\u27kmaq First Nation cosmology: investigating the practice of contemporary Aboriginal Traditional Medicine in dialogue with counselling – toward an Indigenous therapeutics

This paper explores from a Mi’kmaq and Aboriginal standpoint foundational knowledge in Indigenous therapeutics. Based on an eco-social-psycho-spiritual way of working, the article proposes Indigenous cultural models that open a window to a rich cultural repository of meanings associated with Indigenous cosmology, ontology and epistemology. The three layers of meaning, theory and practice within the symbolic ‘Medicine Lodge’ or ‘Place of The Dreaming’ give rise to ways of working that are deeply integrative and wholistic. These forms of Indigenous theory and practice have much to offer the counselling and complimentary health professions

How Can We Support the Use of Oral PrEP Among Young Women who Sell Sex? A PrEP Cascade Analysis.

BACKGROUND: We constructed self-reported pre-exposure prophylaxis (PrEP) cascades and explored factors associated with and barriers to PrEP use to inform efforts to support PrEP use among young women who sell sex. METHODS: Using self-reported data from HIV-negative young women who sell sex enrolled into a cohort study using respondent-driven sampling in Zimbabwe, we constructed PrEP cascades assessing knowledge of, ever offered, ever used, and current PrEP use in 2017 and 2019. We used logistic regression to examine factors associated with PrEP use by 2019. Through qualitative interviews with 43 women enrolled in the cohort, we investigated barriers to PrEP use. RESULTS: At enrollment, 50% of women had heard of PrEP, 12% had ever been offered PrEP, and 7% ever used PrEP. Over time, all cascade domains: 96% of women had heard of and 55% reported an active offer of PrEP. Among women retained in the study in 2019 (56%; n = 538), 34% ever took PrEP by 2019. PrEP use was associated with, at enrollment, reporting more clients in the past month (10+: 45% vs 1-3: 27% adjOR = 1.71 95% CI: 1.06 to 2.76), duration of selling sex (24% <2 years vs 38% 2-3 years; adjOR = 0.51 95% CI: 0.32 to 0.83), and having visited a female sex worker program in the past 12 months (55% vs 27%; adjOR = 2.92 95% CI: 1.91 to 4.46). Qualitative interviews revealed fear of disclosing sex work, HIV-related/ART-related stigma, and (opportunity) costs of accessing PrEP as barriers to use. CONCLUSION: PrEP use was associated with factors known to increase HIV risk. Fear of stigma, disclosure, and supply-side barriers need to be addressed to increase women's ability to use PrEP

Two new rapid SNP-typing methods for classifying Mycobacterium tuberculosis complex into the main phylogenetic lineages

There is increasing evidence that strain variation in Mycobacterium tuberculosis complex (MTBC) might influence the outcome of tuberculosis infection and disease. To assess genotype-phenotype associations, phylogenetically robust molecular markers and appropriate genotyping tools are required. Most current genotyping methods for MTBC are based on mobile or repetitive DNA elements. Because these elements are prone to convergent evolution, the corresponding genotyping techniques are suboptimal for phylogenetic studies and strain classification. By contrast, single nucleotide polymorphisms (SNP) are ideal markers for classifying MTBC into phylogenetic lineages, as they exhibit very low degrees of homoplasy. In this study, we developed two complementary SNP-based genotyping methods to classify strains into the six main human-associated lineages of MTBC, the 'Beijing' sublineage, and the clade comprising Mycobacterium bovis and Mycobacterium caprae. Phylogenetically informative SNPs were obtained from 22 MTBC whole-genome sequences. The first assay, referred to as MOL-PCR, is a ligation-dependent PCR with signal detection by fluorescent microspheres and a Luminex flow cytometer, which simultaneously interrogates eight SNPs. The second assay is based on six individual TaqMan real-time PCR assays for singleplex SNP-typing. We compared MOL-PCR and TaqMan results in two panels of clinical MTBC isolates. Both methods agreed fully when assigning 36 well-characterized strains into the main phylogenetic lineages. The sensitivity in allele-calling was 98.6% and 98.8% for MOL-PCR and TaqMan, respectively. Typing of an additional panel of 78 unknown clinical isolates revealed 99.2% and 100% sensitivity in allele-calling, respectively, and 100% agreement in lineage assignment between both methods. While MOL-PCR and TaqMan are both highly sensitive and specific, MOL-PCR is ideal for classification of isolates with no previous information, whereas TaqMan is faster for confirmation. Furthermore, both methods are rapid, flexible and comparably inexpensive

Recollecting positive and negative autobiographical memories disrupts working memory.

The present article reports two experiments examining the impact of recollecting emotionally valenced autobiographical memories on subsequent working memory (WM) task performance. Experiment 1 found that negatively valenced recollection significantly disrupted performance on a supra-span spatial WM task. Experiment 2 replicated and extended these findings to a verbal WM task (digit recall), and found that both negative and positive autobiographical recollections had a detrimental effect on verbal WM. In addition, we observed that these disruptive effects were more apparent on early trials, immediately following autobiographical recollection. Overall, these findings show that both positive and negative affect can disrupt WM when the mood-eliciting context is based on autobiographical memories. Furthermore, these results indicate that the emotional disruption of WM can take place across different modalities of WM (verbal and visuo-spatial

Is the superior verbal memory span of Mandarin speakers due to faster rehearsal?

It is well established that digit span in native Chinese speakers is atypically high. This is commonly attributed to a capacity for more rapid subvocal rehearsal for that group. We explored this hypothesis by testing a group of English-speaking native Mandarin speakers on digit span and word span in both Mandarin and English, together with a measure of speed of articulation for each. When compared to the performance of native English speakers, the Mandarin group proved to be superior on both digit and word spans while predictably having lower spans in English. This suggests that the Mandarin advantage is not limited to digits. Speed of rehearsal correlated with span performance across materials. However, this correlation was more pronounced for English speakers than for any of the Chinese measures. Further analysis suggested that speed of rehearsal did not provide an adequate account of differences between Mandarin and English spans or for the advantage of digits over words. Possible alternative explanations are discussed

How Can Programs Better Support Female Sex Workers to Avoid HIV Infection in Zimbabwe? A Prevention Cascade Analysis

BACKGROUND: “HIV prevention cascades” have been proposed to support programs by identifying gaps in demand for, access to, and capability to adhere to HIV prevention tools, but there are few empirical examples to guide development. We apply a prevention cascade framework to examine prevention coverage and factors associated with condoms and/or PrEP adherence among female sex workers. SETTING: Seven sites across Zimbabwe. METHODS: Seven respondent-driven sampling surveys from the intervention sites of a pragmatic cluster-randomized trial in Zimbabwe in 2016 were analyzed, and 611/1439 women testing HIV-negative included. We operationalized key components of an HIV prevention cascade including demand, supply, and capability to adhere to 2 tools for HIV prevention: condoms and pre-exposure prophylaxis (PrEP). We used adjusted logistic regression to identify determinants of adherence to condoms and PrEP in turn, examining the effect of adherence to one tool on adherence to the other. RESULTS: There were 343/611, 54.7%, women reporting adherence to condoms and/or PrEP, leaving almost half uncovered. Although women were aware that condoms prevented HIV and reported good access to them, only 45·5% reported full adherence to condom use. For PrEP, a new technology, there were gaps along all 3 domains of demand, supply, and adherence. Alcohol use decreased adherence to PrEP and condoms. Younger and newer entrants to sex work were less likely to take PrEP every day. CONCLUSIONS: HIV prevention programming among female sex workers in Zimbabwe could consider increasing awareness of PrEP alongside supply, alcohol use interventions, and approaches to engaging younger women