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Defects in DNA repair frequently lead to neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of DNA repair in long-lived post-mitotic neurons 1 , 2 . The cellular genome is subjected to a constant barrage of endogenous DNA damage, but surprisingly little is known about the identity of the lesion(s) that accumulate in neurons and whether they accrue throughout the genome or at specific loci. Here we show that post-mitotic neurons accumulate unexpectedly high levels of DNA single-strand breaks (SSBs) at specific sites within the genome. Genome-wide mapping reveals that SSBs are located within enhancers at or near CpG dinucleotides and sites of DNA demethylation. These SSBs are repaired by PARP1 and XRCC1-dependent mechanisms. Notably, deficiencies in XRCC1-dependent short-patch repair increase DNA repair synthesis at neuronal enhancers, whereas defects in long-patch repair reduce synthesis. The high levels of SSB repair in neuronal enhancers are therefore likely to be sustained by both short-patch and long-patch processes. These data provide the first evidence of site- and cell-type-specific SSB repair, revealing unexpected levels of localized and continuous DNA breakage in neurons. In addition, they suggest an explanation for the neurodegenerative phenotypes that occur in patients with defective SSB repair. DNA single-strand breaks in neurons accumulate at high levelsin functional enhancers.

BackgroundWhile price increases and targeted cessation support have been found to reduce inequalities in smoking by socioeconomic status (SES), evidence on other measures is mixed. We aimed to update the most recent (2014) previous review by identifying and appraising evidence published since 2013 on the equity impact of population tobacco control measures.MethodsSystematic searching of 10 electronic databases and hand-searching of four key journals identified 68 primary research articles published since 2013 that sought to examine the equity impact of population tobacco control measures in high-income countries with a negative socioeconomic gradient in smoking. Reported equity impacts were categorised as positive (greater impact among lower SES), neutral (no difference by SES), negative (greater impact among higher SES) or mixed/unclear.ResultsThere was substantial growth in research seeking to evaluate the equity impact of tobacco control interventions, but the majority of new studies showed mixed/unclear results. Findings for price increases and targeted cessation support continue to suggest an equity-positive impact, but limitations in the available evidence make further assessment difficult. Substantial differences in the context, scale and implementation of tobacco control policies make straightforward comparison of findings from the previous 2014 and current reviews problematic.ConclusionResearchers need to adopt more sophisticated, multidisciplinary approaches in evaluating the equity impact of tobacco control measures—developing robust measures of equity effect and using frameworks that take account of context, existing systems/processes and the likely mechanisms of action. Socioeconomic differences in intervention impact within low-income and middle-income countries require evaluation.

Autophagy is essential for cellular homeostasis and function. In neurons, autophagosome biogenesis is temporally and spatially regulated to occur near presynaptic sites, in part via the trafficking of autophagy transmembrane protein ATG-9. The molecules that regulate autophagy by sorting ATG-9 at synapses remain largely unknown. Here, we conduct forward genetic screens at single synapses of C . elegans neurons and identify a role for the long isoform of the active zone protein Clarinet (CLA-1L) in regulating sorting of autophagy protein ATG-9 at synapses, and presynaptic autophagy. We determine that disrupting CLA-1L results in abnormal accumulation of ATG-9 containing vesicles enriched with clathrin. The ATG-9 phenotype in cla-1(L) mutants is not observed for other synaptic vesicle proteins, suggesting distinct mechanisms that regulate sorting of ATG-9-containing vesicles and synaptic vesicles. Through genetic analyses, we uncover the adaptor protein complexes that genetically interact with CLA-1 in ATG-9 sorting. We also determine that CLA-1L extends from the active zone to the periactive zone and genetically interacts with periactive zone proteins in ATG-9 sorting. Our findings reveal novel roles for active zone proteins in the sorting of ATG-9 and in presynaptic autophagy.

Background: With multi-stakeholder approaches central to efforts to address global health challenges, debates around conflict of interest (COI) are increasingly prominent. The World Health Organization (WHO) recently developed a proposed tool to support member states in preventing and managing COI in nutrition policy. We analysed responses to an online consultation to explore how actors from across sectors understand COI and the ways in which they use this concept to frame the terms of commercial sector engagement in health governance. Methods: Submissions from 44 Member States, international organisations, non-governmental organizations (NGOs), academic institutions and commercial sector actors were coded using a thematic framework informed by framing theory. Respondents’ orientation to the tool aligned with two broad frames, ie, a ‘collaboration and partnership’ frame that endorsed multi-stakeholder approaches and a ‘restricted engagement’ frame that highlighted core tensions between public health and food industry actors. Results: Responses to the WHO tool reflected contrasting conceptualisations of COI and implications for health governance. While most Member States, NGOs, and academic institutions strongly supported the tool, commercial sector organisations depicted it as inappropriate, unworkable and incompatible with the Sustainable Development Goals (SGDs). Commercial sector respondents advanced a narrow, individual-level understanding of COI, seen as adequately addressed by existing mechanisms for disclosure, and viewed the WHO tool as unduly restricting scope for private sector engagement in nutrition policy. In contrast, health-focused NGOs and several Member States drew on a more expansive understanding of COI that recognised scope for wider tensions between public health goals and commercial interests and associated governance challenges. These submissions mostly welcomed the tool as an innovative approach to preventing and managing such conflicts, although some NGOs sought broader exclusion of corporate actors from policy engagement. Conclusion: Submissions on the WHO tool illustrate how contrasting positions on COI are central to understanding broader debates in nutrition policy and across global health governance. Effective health governance requires greater understanding of how COI can be conceptualised and managed amid high levels of contestation on policy engagement with commercial sector actors. This requires both ongoing innovation in governance tools and more extensive conceptual and empirical research.

In the current research, we used data from a sample of 16,327 menstrual cycle tracking app users to examine the association between menstrual cycle characteristics and sexual motivation tracked over 10 months of app use. Guided by past work that finds links between menstrual cycle characteristics related to conception risk and sexual motivation, we found that (a) between-women, shorter ( r  = − 0.04, p  = 0.007), more regular cycles predicted small increases in sexual motivation ( r  = − 0.04, p  = 0.001); (b) within-women, shorter cycles predicted greater sexual motivation that month ( r  = − 0.04, p  < 0.001) and (c) the next month ( β s: − 0.10 to − 0.06, p s < 0.001), but (d) changes in sexual motivation did not reliably precede changes in cycle length ( β s: − 0.01 to 0.02, p s > 0.15). Within-woman analyses also revealed that (e) shorter cycles were followed by more frequent reports of fatigue ( β  = − 0.06, p  < 0.001), insomnia ( β  = − 0.03, p  < 0.001), and food cravings ( β  = − 0.04, p  < 0.001). Together, results suggest that menstrual cycles characteristics and sexual motivation may covary together in ways that reflect changing investments in reproduction. Small effect sizes and lack of experimental control warrant cautious interpretations of results.

Public health's terms of engagement with unhealthy commodity industries (alcohol, tobacco and ultra-processed food and drinks) have become increasingly contested in policy and research. We sought to identify approaches that could attract consensus support within and across policy domains. Using snowball sampling, we undertook an online survey of 335 health researchers, advocates and policymakers, in 40 countries, assessing responses to stated principles, claims and recommendations for engaging with unhealthy commodity industries in relation to key policy and research initiatives. Most respondents identified a fundamental conflict between industry interests and public health objectives for all three industries, with agreement greatest in relation to tobacco and weakest for food. This pattern was replicated across diverse questions regarding potential forms of engagement, including in rejecting voluntarism and partnership approaches to health policy. While awareness of tobacco industry tactics to influence policy and research was higher than for alcohol and food, most respondents rejected the view that the influence of the latter was less significant for public health. Proposals that health and research organisations should divest their funds attracted less support with respect to food, while restricting publication of industry-funded research in academic journals was the issue that most divided opinion. Respondents reported most difficulty in answering questions about the food industry. The strong consensus around restricting interactions with the tobacco industry supports increased implementation of the WHO Framework Convention on Tobacco Control's conflict of interest provisions. There is strong support for the extension of such practices to the alcohol industry, challenging current norms. More mixed responses indicate a need for greater clarity in defining the food industry, and for research analyzing links, similarities and differences across different types of unhealthy commodity producers. Partnership approaches to addressing non-communicable diseases seem incapable of attracting widespread support across public health, challenging practice in many contexts.

Background Several governments have introduced taxes on products with high sugar content as part of their obesity prevention strategies. Bermuda is the first jurisdiction to apply such measures in the Caribbean – a region of small island developing states and territories with high obesity prevalence and substantial reliance on imported food products. This study examines how commercial and health actors framed the proposed introduction of a 75% import tariff on high-sugar products, based on written submissions to the Bermudan government. Methods Eleven submissions containing written comments were analysed with reference to their framing of the proposed import tariff, the ‘problem’ of obesity, and the relationship between the two (including alternative policy approaches for tackling obesity). Results Key emergent frames were complexity , partnership , products , personal responsibility , affordability and evidence . Respondents favoured different framings, depending on whether they supported or opposed the proposed import duty. Commercial actors were universally opposed, presenting obesity as a ‘complex’ problem that would be better addressed through government-industry partnerships (a framing particularly favoured by international and regional business associations). Increased product range and an emphasis on personal responsibility were also positioned as policy alternatives. Health actors expressed partial support for the proposed sugar tax, although this was tempered by a perceived lack of evidence where the proposal differed from sugar taxes introduced elsewhere. Like commercial respondents, health actors framed obesity as a ‘complex’ problem and emphasised the need for other measures, including efforts to address the affordability of fruits and vegetables. Conclusion In responding to a proposed ‘sugar tax’ in Bermuda, commercial actors opposed the proposal and stated a clear preference for ‘partnership’ approaches to tackling obesity. Commercial responses were dominated by local businesses (with only two responses received from international or regional business associations), perhaps reflecting Bermuda’s reliance on tourism and hospitality and the specificity of the proposed intervention (that is, an import tariff rather than an excise tax). The much smaller number of responses from health actors suggests limited civil society capacity. Nevertheless, the Bermudan government successfully introduced a 75% tariff on high-sugar imports, demonstrating the potential for policy innovation to address obesity in small-island jurisdictions.

The pace and trajectory of global and local environmental changes are jeopardizing our health in numerous ways, among them exacerbating the risk of disease emergence and spread in both the community and the healthcare setting via healthcare-associated infections (HAIs). Factors such as climate change, widespread land alteration, and biodiversity loss underlie changing human–animal–environment interactions that drive disease vectors, pathogen spillover, and cross-species transmission of zoonoses. Climate change–associated extreme weather events also threaten critical healthcare infrastructure, infection prevention and control (IPC) efforts, and treatment continuity, adding to stress to strained systems and creating new areas of vulnerability. These dynamics increase the likelihood of developing antimicrobial resistance (AMR), vulnerability to HAIs, and high-consequence hospital-based disease transmission. Using a One Health approach to both human and animal health systems, we can become climate smart by re-examining impacts on and relationships with the environment. We can then work collaboratively to reduce and respond to the growing threat and burden of infectious diseases.

Early life stress increases one’s risk for health problems later in life, and many studies find that these effects are sex-differentiated. Here, we examined relationships between multiple sources of early life stress and adult immune function in humans across several functional assays. Adult participants provided retrospective information about their childhood (a) socioeconomic status, (b) household unpredictability, and (c) exposure to adverse experiences. Participants’ peripheral blood mononuclear cells (PBMCs) were then isolated for use in functional assays of immune performance: (a) tumor cell lysis by natural killer cells, (b) phagocytosis of Escherichia coli bioparticles, and (c) mitogen-induced leukocyte proliferation and cytokine release. In men, lower childhood socioeconomic status predicted decrements in immunological performance across functional assays, along with greater spontaneous cytokine release from PBMCs. These changes co-occurred with elevations in plasma testosterone levels. Similar effects were not observed for other sources of stress, nor were they found in women (with the exception of spontaneous cytokine release). These findings provide evidence that low childhood socioeconomic status has a lasting negative impact on multiple aspects of immune function, particularly in men.

Here, we present a mechanistically grounded theory detailing a novel function of the behavioral immune system (BIS), the psychological system that prompts pathogen avoidance behaviors. We propose that BIS activity allows the body to downregulate basal inflammation, preventing resultant oxidative damage to DNA and promoting longevity. Study 1 investigated the relationship between a trait measure of pathogen avoidance motivation and in vitro and in vivo proinflammatory cytokine production. Study 2 examined the relationship between this same predictor and DNA damage often associated with prolonged inflammation. Results revealed that greater trait pathogen avoidance motivation predicts a) lower levels of spontaneous (but not stimulated) proinflammatory cytokine release by peripheral blood mononuclear cells (PBMCs), b) lower plasma levels of the proinflammatory cytokine interleukin-6 (IL-6), and c) lower levels of oxidative DNA damage. Thus, the BIS may promote health by protecting the body from the deleterious effects of inflammation and oxidative stress.