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Catalysing change in health and medical research policy: an Australian case study of deliberative democracy to reform sex and gender policy recommendations
No full textRevising public health policy based on new data does not happen automatically. This is acutely relevant to the now undeniable evidence that many diseases develop differently between the sexes and may also be affected by gender. Current health and medical practices across the globe generally fail to cater for sex and gender effects in common diseases. Inadequate policy frameworks to guide the comprehensive inclusion of sex and gender in research jeopardises scientific rigour and ultimately the practices they underpin. To ensure that Australian health and medical research is fit-for-purpose, we realised that potent initiatives would be necessary to expedite strategic reframing of thought and behaviour. Here we report on our innovative engagement of end-users for democratic self-determined policy reform to guide health and medical research, based on robust data. We draw upon our specific study to outline seven key steps that can be adopted to accelerate effective change, across a breadth of evidence-based initiatives to reform health policies
Annual Blood Tests Are an Acceptable form of Surveillance to Supplement Colonoscopies for Colorectal Cancer
No full textBACKGROUND: Individuals at increased risk of colorectal cancer (CRC) are recommended surveillance colonoscopies as a preventative measure, but timely provision of colonoscopies remains a significant hurdle. Biomarker testing has emerged as a potential strategy to mitigate excessive colonoscopy use by prioritizing procedures for those most at risk of CRC. However, the acceptability of supplementing surveillance colonoscopies with regular blood tests is unknown. AIM: To evaluate patient acceptance of a hypothetical surveillance protocol providing annual blood tests between 5-yearly colonoscopies. METHODS: Eight hundred individuals enrolled in an Australian surveillance colonoscopy program were invited to complete a survey on surveillance preferences. Ordinal logistic regression analysis was performed to assess the influence of sociodemographic, clinical, and psychological variables on participants' comfort with the surveillance protocol. RESULTS: A total of 409 (51%) individuals participated, with 346 (51% male, mean age 63 years) providing complete outcome data. Most participants (n = 250/346, 72%) reported being comfortable with the surveillance protocol. Significantly higher levels of comfort were reported by individuals with greater confidence in their ability to undergo blood testing (OR 1.26, 95% CI 1.08-1.47, p = 0.003) and those having less frequent surveillance colonoscopies (OR 1.26, 95% CI 1.01-1.58, p = 0.043). Significant associations were not observed between other variables and comfort with the surveillance protocol (p > 0.05). CONCLUSIONS: Annual blood testing between surveillance colonoscopies was highly accepted by individuals at increased risk of CRC. Offering new blood-based modalities to specific subpopulations, particularly individuals who are more comfortable with blood testing, or those having less frequent surveillance colonoscopies, could enhance overall acceptance
Wolbachia strain wMelM disrupts egg retention by Aedes aegypti females prevented from ovipositing
No full textAedes aegypti mosquitoes are well adapted to dry climates and can retain their eggs for extended periods in the absence of suitable habitat. Wolbachia strains transferred from other insects to mosquitoes can be released to combat dengue transmission by blocking virus replication and spreading through populations, but host fitness costs imposed by Wolbachia, particularly under some environments, can impede spread. We, therefore, assessed the impact of two Wolbachia strains being released for dengue control (wAlbB and wMelM) on fecundity and egg viability following extended egg retention (up to 24 days) under laboratory conditions. Egg viability following retention decreased to a greater extent in females carrying wMelM compared to uninfected or wAlbB females. Fertility fully recovered in uninfected females following a second blood meal after laying retained eggs, while wMelM females experienced only partial recovery. Effects of wMelM on egg retention were similar regardless of whether females were crossed to uninfected or wMelM males, suggesting that fitness costs were triggered by Wolbachia presence in females. The fecundity and hatch proportions of eggs of wMelM females declined with age, regardless of whether females used stored sperm or were recently inseminated. Costs of some Wolbachia strains during egg retention may affect the invasion and persistence of Wolbachia in release sites where larval habitats are scarce and/or intermittent
Embedding lived experience in mental health research: What we need to pack (and unpack) for the future in mental health research and translation
No full textThe incorporation of lived experience in mental health research has been a challenge for decades, pushing the boundaries of research to focus on the priorities of those most impacted. The people who should be the ultimate beneficiaries of research and its translation hold significant knowledge about both the topics of research and the way it should be respectfully conducted. However, despite policy, funding and most recently publishing directives that purport to support genuine lived experience-focused and -led research, progress remains slow, and debates are frequently still dominated by non-lived experience researchers in positions of power. In this paper, we explore some of the factors we need to consider to genuinely progress in mental health lived experience research, including restrictive and exclusionary thinking on authenticity, the ability to speak from multiple perspectives and the deeply personal intersections of experience in lived experience researcher identities. We then describe the ALIVE National Centre Embedded Lived Experience Research Model and an associated National Strategy for Lived Experience in Mental Health Research as responses to these pervasive issues
Age and Latent Cytomegalovirus Infection Do Not Affect the Magnitude of De Novo SARS-CoV-2-Specific CD8+ T Cell Responses
No full textImmunosenescence, age-related immune dysregulation, reduces immunity upon vaccinations and infections. Cytomegalovirus (CMV) infection results in declining naïve (Tnaïve) and increasing terminally differentiated (Temra) T cell populations, further aggravating immune aging. Both immunosenescence and CMV have been speculated to hamper the formation of protective T-cell immunity against novel or emerging pathogens. The SARS-CoV-2 pandemic presented a unique opportunity to examine the impact of age and/or CMV on the generation of de novo SARS-CoV-2-specific CD8+ T cell responses in 40 younger (22–40 years) and 37 older (50–66 years) convalescent individuals. Heterotetramer combinatorial coding combined with phenotypic markers were used to study 35 SARS-CoV-2 epitope-specific CD8+ T cell populations directly ex vivo. Neither age nor CMV affected SARS-CoV-2-specific CD8+ T cell frequencies, despite reduced total CD8+ Tnaïve cells in older CMV- and CMV+ individuals. Robust SARS-CoV-2-specific central memory CD8+ T (Tcm) responses were detected in younger and older adults regardless of CMV status. Our data demonstrate that immune aging and CMV status did not impact the SARS-CoV-2-specific CD8+ T cell response. However, SARS-CoV-2-specific CD8+ T cells of older CMV- individuals displayed the lowest stem cell memory (Tscm), highest Temra and PD1+ populations, suggesting that age, not CMV, may impact long-term SARS-CoV-2 immunity
Physical Activity during Adolescence and Early Adulthood and Breast Cancer Risk before Age 40 Years
No full textBACKGROUND: Breast cancer incidence is increasing in women under age 40, underscoring the need for research on breast cancer risk factors for younger women. METHODS: We used data from an international family cohort (n = 26,348) to examine whether recreational physical activity (RPA) during adolescence and early adulthood is associated with breast cancer risk before age 40. The cohort includes 2,502 women diagnosed with breast cancer before age 40, including 2,408 diagnosed before study enrollment (68% within 5 years of enrollment). Women reported their average hours per week of moderate and strenuous RPA during adolescence (12-17 years) and early adulthood (25-34 years), which were converted to total age-adjusted metabolic equivalents per week and categorized into quartiles. We conducted attained age analyses until age 40 (follow-up time began at age 18) using Cox proportional hazards regression models adjusted for study center, race and ethnicity, and education. RESULTS: Being in the highest versus lowest quartile of RPA during adolescence and early adulthood were respectively associated with 12% [HR (95% confidence interval, or CI), 0.88 (0.78-0.98)] and 16% [HR (95% CI), 0.84 (0.74-0.95) lower breast cancer risks before age 40. Being in the highest quartile of RPA during both adolescence and early adulthood (Pearson correlation = 0.52) versus neither time point was associated with a 22% lower risk [HR (95% CI), 0.78 (0.68-0.89)]. CONCLUSIONS: Findings suggest that RPA during adolescence and early adulthood may lower breast cancer risk before age 40. IMPACT: Policies promoting physical activity during adolescence and early adulthood may be important for reducing the growing burden of breast cancer in younger women
Chemical Genetics of P. falciparum Plasmepsin V, Plasmepsin X, and Cytochrome b
No full text© 2025 Wenyin SuMalaria is caused by the Plasmodium parasite and results in about 600,000 deaths worldwide annually. The emergence of resistance against almost all antimalarial drugs has now become an obstacle to eliminating the disease. To address the issue, there is an urgent need for the discovery and development of new antimalarials with novel mechanisms of action. In this thesis, complementary forward and reverse genetics, and chemo-proteomic techniques were applied to characterise the mechanism of action (MoA) and explore resistance factors of three antimalarial classes.
Plasmepsin V (PMV) is an aspartyl protease that is essential for processing the N-terminal PEXEL motif of proteins licensing them for export to the host red blood cell during the asexual segment of malaria parasite’s life cycle. Small molecule peptidomimetics mimicking the PEXEL motif have been previously developed as potent inhibitors of PMV. The peptidomimetics have been shown to block protein export and kill the malaria parasite, although confirmation of their on-target activity was required. In Chapter 2, resistance selection and genome sequencing revealed a mutation in PMV. Reverse genetics was then used to reverse engineer parasites to confirm the mutation in PMV. Biased and unbiased chemo-proteomics were then applied to demonstrate on-target engagement of PMV in P. falciparum parasites, definitively showing that the peptidomimetics kill the parasite by targeting PMV.
Plasmepsin X (PMX) is an aspartyl protease that is vital for the maturation of proteins that enable the malaria parasite to enter and exit from the host red blood cell. Small molecules with an imino pyrimidinone chemotype have been developed as inhibitors of PMX that potently block red blood cell invasion and egress preventing asexual stage parasite development. Resistance selection using imino pyrimidinone inhibitors was previously performed to understand the risk of resistance in the field. In Chapter 3, parasites were genetically reversed engineered to confirm and investigate the mutations and amplifications in PMX responsible for the resistance observed.
To uncover new starting points for antimalarial development, a phenotypic screen of the Janssen Jumpstarter library against the asexual stage parasite uncovered the cyclopropyl carboxamide hit class. In Chapter 4, forward genetics was used to identify the MoA of the hit class. Genome sequencing of cyclopropyl carboxamide-resistant parasites revealed mutations in the Qo site of cytochrome b, which is an essential component of the mitochondrial electron transport chain. Cytochrome b was confirmed as the molecular target by evaluating cyclopropyl carboxamide analogs against cytochrome b resistant parasite lines, and in a mitochondrial functional assay supporting this antimalarial class targeting cytochrome b.
The investigation of the mechanisms of action of the three antimalarial classes undertaken in this thesis will assist in better understanding the role of the target proteins in parasite survival and resistance to facilitate the future development of these antimalarial classes
Molecular determinants of Neu5Ac binding to a tripartite ATP independent periplasmic (TRAP) transporter
No full textN -Acetylneuraminic acid (Neu5Ac) is a negatively charged nine-carbon amino sugar that is often the peripheral sugar in human cell-surface glycoconjugates. Some bacteria scavenge, import, and metabolize Neu5Ac or redeploy it on their cell surfaces for immune evasion. The import of Neu5Ac by many bacteria is mediated by tripartite ATP-independent periplasmic (TRAP) transporters. We have previously reported the structures of SiaQM, a membrane-embedded component of the Haemophilus influenzae TRAP transport system, (Currie et al., 2024). However, none of the published structures contain Neu5Ac bound to SiaQM. This information is critical for defining the transport mechanism and for further structure-activity relationship studies. Here, we report the structures of Fusobacterium nucleatum SiaQM with and without Neu5Ac. Both structures are in an inward (cytoplasmic side) facing conformation. The Neu5Ac-bound structure reveals the interactions of Neu5Ac with the transporter and its relationship with the Na+ binding sites. Two of the Na+-binding sites are similar to those described previously. We identify a third metal-binding site that is further away and buried in the elevator domain. Ser300 and Ser345 interact with the C1-carboxylate group of Neu5Ac. Proteoliposome-based transport assays showed that Ser300-Neu5Ac interaction is critical for transport, whereas Ser345 is dispensable. Neu5Ac primarily interacts with residues in the elevator domain of the protein, thereby supporting the elevator with an operator mechanism. The residues interacting with Neu5Ac are conserved, providing fundamental information required to design inhibitors against this class of proteins
An integrated structural and biophysical approach to study carbon metabolism in Mycobacterium tuberculosis
No full textMetabolic enzymes are the catalysts that drive the biochemical reactions essential for sustaining life. Many of these enzymes are tightly regulated by feedback mechanisms. To fully understand their roles and modulation, it is crucial to investigate the relationship between their structure, catalytic mechanism, and function. In this perspective, by using three examples from our studies on Mycobacterium tuberculosis (Mtb) isocitrate lyase and related proteins, we highlight how an integrated approach combining structural, activity, and biophysical data provides insights into their biological functions. These examples underscore the importance of employing fast-fail experiments at the early stages of a research project, emphasise the value of complementary techniques in validating findings, and demonstrate how in vitro data combined with chemical, biochemical, and physiological knowledge can lead to a broader understanding of metabolic adaptations in pathogenic bacteria. Finally, we address the unexplored questions in Mtb metabolism and discuss how we expand our approach to include microbiological and bioanalytical techniques to further our understanding. Such an integrated and interdisciplinary strategy has the potential to uncover novel regulatory mechanisms and identify new therapeutic opportunities for the eradication of tuberculosis. The approach can also be broadly applied to investigate other biochemical networks and complex biological systems