Microglial inflammation in genome instability: A neurodegenerative perspective.

The maintenance of genome stability is crucial for cell homeostasis and tissue integrity. Numerous human neuropathologies display chronic inflammation in the central nervous system, set against a backdrop of genome instability, implying a close interplay between the DNA damage and immune responses in the context of neurological disease. Dissecting the molecular mechanisms of this crosstalk is essential for holistic understanding of neuroinflammatory pathways in genome instability disorders. Non-neuronal cell types, specifically microglia, are major drivers of neuroinflammation in the central nervous system with neuro-protective and -toxic capabilities. Here, we discuss how persistent DNA damage affects microglial homeostasis, zooming in on the cytosolic DNA sensing cGAS-STING pathway and the downstream inflammatory response, which can drive neurotoxic outcomes in the context of genome instability.

Psychological ownership and identity motives in blood donation.

BACKGROUND AND OBJECTIVES: Interventions to retain existing donors are essential to increase the blood supply. Blood donor self-identity is proposed to motivate sustained donation behaviour. However, interventions to develop self-identity in the absence of donating blood are scarce. We propose that experiencing psychological ownership of a blood collection agency (BCA) may provide a potential avenue for fostering donor self-identity and subsequent sustained donation behaviour. MATERIALS AND METHODS: Two hundred and fifty-five donor participants were recruited through Prolific Academic (n = 175) and an Australian online blood donor community group (n = 80), with an additional 252 non-donors recruited through Prolific Academic. Participants completed an online survey assessing donation behaviour, perceived psychological ownership of a BCA, self-identity and intentions to donate blood, amongst other constructs. RESULTS: Consistent with our theoretical argument, psychological ownership was positively associated with self-identity, which, in turn, was positively associated with intentions to donate blood. Donation behaviour was positively associated with psychological ownership. Examination of psychological ownership by donation experience showed the expected relationship with committed donors having the strongest psychological ownership and non-donors having the weakest psychological ownership over a BCA. CONCLUSION: We provide initial support for the inclusion of psychological ownership within a model of sustained blood donation behaviour.

Comparison of tumor-informed and tumor-naïve sequencing assays for ctDNA detection in breast cancer.

Analysis of circulating tumor DNA (ctDNA) to monitor cancer dynamics and detect minimal residual disease has been an area of increasing interest. Multiple methods have been proposed but few studies have compared the performance of different approaches. Here, we compare detection of ctDNA in serial plasma samples from patients with breast cancer using different tumor-informed and tumor-naïve assays designed to detect structural variants (SVs), single nucleotide variants (SNVs), and/or somatic copy-number aberrations, by multiplex PCR, hybrid capture, and different depths of whole-genome sequencing. Our results demonstrate that the ctDNA dynamics and allele fractions (AFs) were highly concordant when analyzing the same patient samples using different assays. Tumor-informed assays showed the highest sensitivity for detection of ctDNA at low concentrations. Hybrid capture sequencing targeting between 1,347 and 7,491 tumor-identified mutations at high depth was the most sensitive assay, detecting ctDNA down to an AF of 0.00024% (2.4 parts per million, ppm). Multiplex PCR targeting 21-47 tumor-identified SVs per patient detected ctDNA down to 0.00047% AF (4.7 ppm) and has potential as a clinical assay.

CRISPR-Cas9 genetic screen leads to the discovery of L-Moses, a KAT2B inhibitor that attenuates Tunicamycin-mediated neuronal cell death.

Accumulation of aggregated and misfolded proteins, leading to endoplasmic reticulum stress and activation of the unfolded protein response, is a hallmark of several neurodegenerative disorders, including Alzheimer's and Parkinson's disease. Genetic screens are powerful tools that are proving invaluable in identifying novel modulators of disease associated processes. Here, we performed a loss-of-function genetic screen using a human druggable genome library, followed by an arrayed-screen validation, in human iPSC-derived cortical neurons. We identified and genetically validated 13 genes, whose knockout was neuroprotective against Tunicamycin, a glycoprotein synthesis inhibitor widely used to induce endoplasmic reticulum stress. We also demonstrated that pharmacological inhibition of KAT2B, a lysine acetyltransferase identified by our genetic screens, by L-Moses, attenuates Tunicamycin-mediated neuronal cell death and activation of CHOP, a key pro-apoptotic member of the unfolded protein response in both cortical and dopaminergic neurons. Follow-up transcriptional analysis suggested that L-Moses provided neuroprotection by partly reversing the transcriptional changes caused by Tunicamycin. Finally, L-Moses treatment attenuated total protein levels affected by Tunicamycin, without affecting their acetylation profile. In summary, using an unbiased approach, we identified KAT2B and its inhibitor, L-Moses, as potential therapeutic targets for neurodegenerative diseases.

Simple Reciprocal Fairness Message to Enhance Non-Donor's Willingness to Donate Blood.

BACKGROUND: Against a background of declining blood donor numbers, recruiting new donors is critical for the effective operations of healthcare providers. Thus, interventions are needed to recruit new blood donors. PURPOSE: We provide initial evidence for Voluntary Reciprocal Altruism (VRA) to enhance nondonors' willingness to become blood donors. VRA interventions involve asking two questions: one on accepting a blood transfusion if needed and one on willingness to donate. As early trials often use self-reports of willingness to perform blood donation behavior, we derive a correction factor to better estimate actual behavior. Finally, we explore the effect of VRA interventions on two prosocial emotions: gratitude and guilt. METHODS: Across three experiments (two in the UK and one in Australia: Total N = 1,208 nondonors) we manipulate VRA messages and explore how they affect both reported willingness to make a one-off or repeat blood donation and influence click through to blood donation, organ donation and volunteering registration sites (behavioral proxies). We report data from a longitudinal cohort (N = 809) that enables us to derive a correction for self-reported behavioral willingness. RESULTS: Across the three experiments, we show that exposure to a question that asks about accepting a transfusion if needed increased willingness to donate blood with some spillover to organ donor registration. We also show that gratitude has an independent effect on donation and report a behavioral correction factor of .10. CONCLUSIONS: Asking nondonors about accepting a transfusion if needed is likely to be an effective strategy to increase new donor numbers.

Australian Perspectives on Opt-In and Opt-Out Consent Systems for Deceased Organ Donation.

Introduction: As many countries change to opt-out systems to address organ shortages, calls for similar reform in Australia persist. Community perspectives on consent systems for donation remain under-researched, therefore Australian perspectives on consent systems and their effectiveness in increasing donation rates were explored. Design: In this descriptive cross-sectional study, participants completed a survey presenting opt-in, soft opt-out, and hard opt-out systems, with corresponding descriptions. Participants chose the system they perceived as most effective and described their reasoning. Results: Participants (N = 509) designated soft opt-out as the most effective system (52.3%; hard opt-out 33.7%; opt-in 13.7%). Those who identified with an ethnic/cultural group or were not registered had greater odds of choosing opt-out. Six themes identified in thematic analysis reflected their reasoning: (1) who decides (individual, shared decision with family); (2) right to choose; (3) acceptability (ethics, fairness); and utility in overcoming barriers for (4) individuals (apathy, awareness, ease of donating, fear/avoidance of death); (5) family (easier family experience, family veto); (6) society (normalizing donation, donation as default, expanding donor pool). Choice and overcoming individual barriers were more frequently endorsed themes for opt-in and opt-out, respectively. Discussion: Results suggested the following insights regarding system effectiveness: uphold/prioritize individual's recorded donation decision above family wishes; involve family in decision making if no donation preference is recorded; retain a register enabling opt-in and opt-out for unequivocal decisions and promoting individual control; and maximize ease of registering. Future research should establish whether systems considered effective are also acceptable to the community to address organ shortages.