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OBJECTIVE: In 2000, a referral hospital in the Gambia accepted a donation of oxygen concentrators to help maintain oxygen supplies. The concentrators broke down and were put into storage. A case study was done to find the reasons for the problem and to draw lessons to help improve both oxygen supplies and the success of future equipment donations. METHODS: A technical assessment of the concentrators was carried out by a biomedical engineer with relevant expertise. Semi-structured interviews were undertaken with key informants, and content analysis and inductive approaches were applied to construct the history of the episode and the reasons for the failure. FINDINGS: Interviews confirmed the importance of technical problems with the equipment. They also revealed that the donation process was flawed, and that the hospital did not have the expertise to assess or maintain the equipment. Technical assessment showed that all units had the wrong voltage and frequency, leading to overheating and breakdown. Subsequently a hospital donations committee was established to oversee the donations process. On-site biomedical engineering expertise was arranged with a nongovernmental organization (NGO) partner. CONCLUSION: Appropriate donations of medical equipment, including oxygen concentrators, can be of benefit to hospitals in resource-poor settings, but recipients and donors need to actively manage donations to ensure that the donations are beneficial. Success requires planning, technical expertise and local participation. Partners with relevant skills and resources may also be needed. In 2002, WHO produced guidelines for medical equipment donations, which address problems that might be encountered. These guidelines should be publicized and used. Copyright © 2008 World Health Organization [ABSTRACT FROM AUTHOR]

Evidence is growing that secondhand smoke can cause death from several diseases. The association between household exposure to secondhand smoke and disease-specific mortality was examined in two New Zealand cohorts of lifelong nonsmokers ('never smokers') aged 45-77 years. Individual census records from 1981 and 1996 were anonymously and probabilistically linked with mortality records from the 3 years that followed each census. Age- and ethnicity-standardized mortality rates were compared for never smokers with and without home exposure to secondhand smoke (based on the reported smoking behavior of other household members). Relative risk estimates adjusted for age, ethnicity, marital status, and socioeconomic position showed a significantly greater mortality risk for never smokers living in households with smokers, with excess mortality attributed to tobacco-related diseases, particularly ischemic heart disease and cerebrovascular disease, but not lung cancer. Adjusted relative risk estimates for all cardiovascular diseases were 1.19 (95% confidence interval: 1.04, 1.38) for men and 1.01 (95% confidence interval: 0.88, 1.16) for women from the 1981-1984 cohort, and 1.25 (95% confidence interval: 1.06, 1.47) for men and 1.35 (95% confidence interval: 1.11, 1.64) for women from the 1996-1999 cohort. Passive smokers also had nonsignificantly increased mortality from respiratory disease. Sensitivity analyses indicate that these findings are not due to misclassification bias. [ABSTRACT FROM AUTHOR]

Background: Nearly 40% of unplanned pregnancies in the USA are the result of inconsistent or incorrect contraceptive use. Finding ways to increase women's comfort and satisfaction with contraceptive use is therefore critical to public health. One promising pathway for improving patient outcomes is through the use of digital decision aids that assist women and their physicians in choosing a contraceptive option that women are comfortable with. Testing the ability of these aids to improve patient outcomes is therefore a necessary first step toward incorporating this technology into traditional physician appointments., Purpose: To evaluate the effectiveness of a novel contraceptive decision aid at minimizing decisional conflict and increasing comfort with contraception among adult women., Methods: In total, 310 adult women were assigned to use either the Tuune contraceptive decision aid or a control aid modeled after a leading online contraceptive prescriber's patient intake form. Participants then completed self-report measures of decisional conflict, contraceptive expectations, satisfaction, and contraceptive use intentions. Individual between-subjects analysis of variance (ANOVA) models were used to examine these outcomes., Results: Women using the Tuune decision aid (vs. those using the control aid) reported lower decisional conflict, more positive contraceptive expectations, greater satisfaction with the decision aid and recommendation, and more positive contraceptive use intentions., Conclusions: Use of Tuune improved each of the predicted patient outcomes relative to a control decision aid. Online decision aids, particularly when used alongside physician consultations, may be an effective tool for increasing comfort with contraceptive use., Clinical Trials Registration #: NCT05177783, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT05177783., (© Society of Behavioral Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Many women experience sexual side effects, such as decreased libido, when taking hormonal contraceptives (HCs). However, little is known about the extent to which libido recovers after discontinuing HCs, nor about the timeframe in which recovery is expected to occur. Given that HCs suppress the activities of multiple endogenous hormones that regulate both the ovulatory cycle and women's sexual function, resumption of cycles should predict libido recovery. Here, using a combination of repeated and retrospective measures, we examined changes in sexual desire and partner attraction (among partnered women) across a three-month period in a sample of Natural Cycles users (Survey 1: n = 1596; Survey 2: n = 550) who recently discontinued HCs. We also tested whether changes in these outcomes coincided with resumption of the ovulatory cycle and whether they were associated with additional factors related to HC use (e.g., duration of HC use) or relationship characteristics (e.g., relationship length). Results revealed that both sexual desire and partner attraction, on average, increased across three months after beginning to use Natural Cycles. While the prediction that changes in sexual desire would co-occur with cycle resumption was supported, there was also evidence that libido continued to increase even after cycles resumed. Together, these results offer new insights into relationships between HC discontinuation and women's sexual psychology and lay the groundwork for future research exploring the mechanisms underlying these effects., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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 (βs: - 0.10 to - 0.06, ps < 0.001), but (d) changes in sexual motivation did not reliably precede changes in cycle length (βs: - 0.01 to 0.02, ps > 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., (© 2024. The Author(s).)

HIV-related stigma in healthcare settings remains a key barrier to engaging people living with HIV (PLHIV) in care. This study investigated the association between clinical encounter frequency and HIV-related anticipated, enacted, and internalized stigma among newly-diagnosed PLHIV in Rwanda. From October 2020 to May 2022, we collected data from adult PLHIV on antiretroviral therapy (ART) in Kigali, Rwanda who were participating in a randomized, controlled trial testing early entry into differentiated care at 6 months after ART initiation. We measured anticipated HIV stigma with five-point Likert HIV Stigma Framework measures, enacted stigma with the four-point Likert HIV/AIDS Stigma Instrument, and internalized stigma with the four-point Likert HIV/AIDS Stigma Instrument. We used multivariable linear regression to test the associations between clinical encounter frequency (average inter-visit interval ≥ 50 days vs. < 50 days) and change in mean anticipated, enacted and internalized HIV stigma over the first 12 months in care. Among 93 individuals enrolled, 76 had complete data on encounter frequency and stigma measurements and were included in the present analysis. Mean internalized stigma scores of all participants decreased over the first 12 months in care. Anticipated and enacted stigma scores were low and did not change significantly over time. There was no association between encounter frequency and change in internalized stigma. In this pilot study of newly-diagnosed Rwandan PLHIV with relatively low levels of HIV-related stigma, clinical encounter frequency was not associated with change in stigma. Additional research in diverse settings and with larger samples is necessary to further explore this relationship., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

Studies of folded-to-misfolded transitions using model protein systems reveal a range of unfolding needed for exposure of amyloid-prone regions for subsequent fibrillization. Here, we probe the relationship between unfolding and aggregation for glaucoma-associated myocilin. Mutations within the olfactomedin domain of myocilin (OLF) cause a gain-of-function, namely cytotoxic intracellular aggregation, which hastens disease progression. Aggregation by wild-type OLF (OLF WT ) competes with its chemical unfolding, but only below the threshold where OLF loses tertiary structure. Representative moderate (OLF D380A ) and severe (OLF I499F ) disease variants aggregate differently, with rates comparable to OLF WT in initial stages of unfolding, and variants adopt distinct partially folded structures seen along the OLF WT urea-unfolding pathway. Whether initiated with mutation or chemical perturbation, unfolding propagates outward to the propeller surface. In sum, for this large protein prone to amyloid formation, the requirement for a conformational change to promote amyloid fibrillization leads to direct competition between unfolding and aggregation., (© 2024. The Author(s).)

Women using hormonal contraceptives (HCs) exhibit numerous signs of chronic inflammation, including elevated C-reactive protein levels and greater risk of developing mood and autoimmune disorders. However, users and non-users of HCs often have similar circulating proinflammatory cytokine levels, making the mechanism of association unclear. One possible explanation for this paradox is that HC users exhibit differences in their inflammatory responses to psychosocial stress that, over time, could contribute to chronic inflammation and its pathologies. Here, we tested this possibility by examining women's glucocorticoid, inflammatory, and psychological responses to the Trier Social Stress Test (TSST) in 67 naturally cycling (NC) and 60 oral HC-using women (M age  = 19.31, SD age  = 1.95). As hypothesized, HC users and NC women exhibited different glucocorticoid and proinflammatory cytokine responses to the TSST. For NC women, TSST-induced increases in glucocorticoids were uncommon, and increases in glucocorticoids were accompanied by elevations in IL-6. In contrast, for women using HCs, increases in glucocorticoids in response to the TSST were common, and increases in glucocorticoids were accompanied by increases in TNF-α. HC users and NC women also differed in their psychological responses to the TSST, with HC users reporting elevated stress levels compared to NC women. Together, these results suggest that HC use impacts women's glucocorticoid, inflammatory, and psychological responses to psychosocial stress, potentially contributing to observed differences in these women's mental and physical health., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The aberrant accumulation of tau protein is implicated as a pathogenic factor in many neurodegenerative diseases. Tau seeding may underlie its predictable spread in these diseases. Molecular chaperones can modulate tau pathology, but their effects have mainly been studied in isolation. This study employed a semi-high throughput assay to identify molecular chaperones influencing tau seeding using Tau RD P301S FRET Biosensor cells, which express a portion of tau containing the frontotemporal dementia-related P301S tau mutation fused to a FRET biosensor. Approximately fifty chaperones from five major families were screened using live cell imaging to monitor FRET-positive tau seeding. Among the tested chaperones, five exhibited significant effects on tau in the primary screen. Notably, three of these were from the DnaJ family. In subsequent studies, overexpression of DnaJA2, DnaJB1, and DnaJB6b resulted in significant reductions in tau levels. Knockdown experiments by shRNA revealed an inverse correlation between DnaJB1 and DnaJB6b with tau levels. DnaJB6b overexpression, specifically, reduced total tau levels in a cellular model with a pre-existing pool of tau, partially through enhanced proteasomal degradation. Further, DnaJB6b interacted with tau complexes. These findings highlight the potent chaperone activity within the DnaJ family, particularly DnaJB6b, towards tau., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

The accumulation and aggregation of the microtubule-associated protein tau (tau) into intracellular neuronal tangles are a hallmark of a range of progressive neurodegenerative tauopathies, including Alzheimer's disease (AD), frontotemporal dementia, Pick's disease, and progressive supranuclear palsy. The aberrant phosphorylation of tau is associated with tau aggregates in AD. Members of the heat shock protein 70 kDa (Hsp70) family of chaperones bind directly to tau and modulate tau clearance and aggregation. Small molecules that inhibit the Hsp70 family of chaperones have been shown to reduce the accumulation of tau, including phosphorylated tau. Here, eight analogs of the rhodacyanine inhibitor, JG-98, were synthesized and evaluated. Like JG-98, many of the compounds inhibited ATPase activity of the cytosolic heat shock cognate 70 protein (Hsc70) and reduced total, aggregated, and phosphorylated tau accumulation in cultured cells. Three compounds, representing divergent c log P values, were evaluated for in vivo blood-brain barrier penetration and tau reduction in an ex vivo brain slice model. AL69, the compound with the lowest c log P and the lowest membrane retention in a parallel artificial membrane permeability assay (PAMPA), reduced phosphorylated tau accumulation. Our results suggest that benzothiazole substitutions of JG-98 that increase hydrophilicity may increase the efficacy of these Hsp70 inhibitors to reduce phosphorylated tau.

Objective: To describe a novel orthodontic appliance to prevent pedicle trauma in patients undergoing double-opposing buccal flap surgery for secondary palatal lengthening., Design: Case series., Setting: Cleft and craniofacial clinic, Johns Hopkins Children's Center., Patients, Participants: Four patients undergoing double-opposing buccal flap surgery for repair of velopharyngeal insufficiency., Interventions: Patients were fitted with the device, which consists of a lower lingual holding arch with acrylic bite blocks., Main Outcome Measure: Presence of pedicle trauma postsurgery and tolerability of the device., Results: The appliance was well tolerated in all 4 patients and no biting trauma to the pedicles was observed., Conclusions: A reliable appliance has been developed to prevent biting trauma to the pedicles in patients undergoing double-opposing buccal flap surgery in the permanent dentition stage.

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Xuan et al. This 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.)

FK506 binding protein 51 (FKBP51) is a molecular chaperone that influences stress response. In addition to having an integral role in the regulation of steroid hormone receptors, including glucocorticoid receptor, FKBP51 has been linked with several biological processes including metabolism and neuronal health. Genetic and epigenetic alterations in the gene that encodes FKBP51, FKBP5, are associated with increased susceptibility to multiple neuropsychiatric disorders, which has fueled much of the research on this protein. Because of the complexity of these processes, animal models have been important in understanding the role of FKBP51. This review examines each of the current mouse models of FKBP5, which include whole animal knockout, conditional knockout, overexpression, and humanized mouse models. The generation of each model and observational details are discussed, including behavioral phenotypes, molecular changes, and electrophysiological alterations basally and following various challenges. While much has been learned through these models, there are still many aspects of FKBP51 biology that remain opaque and future studies are needed to help illuminate these current gaps in knowledge. Overall, FKBP5 continues to be an exciting potential target for stress-related disorders., (© 2023 Wiley Periodicals LLC.)

Alzheimer's disease and related tauopathies are characterized by the pathogenic misfolding and aggregation of the microtubule-associated protein tau. Understanding how endogenous chaperones modulate tau misfolding could guide future therapies. Here, we show that the immunophilin FKBP12, the 12-kDa FK506-binding protein (also known as FKBP prolyl isomerase 1A), regulates the neuronal resilience by chaperoning a specific structure in monomeric tau. Using a combination of mouse and cell experiments, in vitro aggregation experiments, nuclear magnetic resonance-based structural analysis of monomeric tau, site-specific phosphorylation and mutation, as well as structure-based analysis using the neural network-based structure prediction program AlphaFold, we define the molecular factors that govern the binding of FKBP12 to tau and its influence on tau-induced neurotoxicity. We further demonstrate that tyrosine phosphorylation of tau blocks the binding of FKBP12 to two highly specific structural motifs in tau. Our data together with previous results demonstrating FKBP12/tau colocalization in neurons and neurofibrillary tangles support a critical role of FKBP12 in regulating tau pathology.

Shifts in normal aging set stage for neurodegeneration and dementia affecting 1 in 10 adults. The study demonstrates that lncRNA GAS5 is decreased in aged and Alzheimer's disease brain. The role and targets of lncRNA GAS5 in the aging brain were elucidated using a GAS5-targeting small molecule NPC86, a frontier in lncRNA-targeting therapeutic. Robust techniques such as molecular dynamics simulation of NPC86 binding to GAS5, in vitro functional assays demonstrating that GAS5 regulates insulin signaling, neuronal survival, phosphorylation of tau, and neuroinflammation via toll-like receptors support the role of GAS5 in maintaining healthy neurons. The study demonstrates the safety and efficacy of intranasal NPC86 treatment in aged mice to improve cellular functions with transcriptomic analysis in response to NPC86. In summary, the study demonstrates that GAS5 contributes to pathways associated with neurodegeneration and NPC86 has tremendous therapeutic potential to prevent the advent of neurodegenerative diseases and dementias., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Women's psychological and behavioral responses to hormonal contraceptive (HC) treatment can be highly variable. One of the great challenges to researchers seeking to improve the experiences of women who use HCs is to identify the sources of this variability to minimize unpleasant psychobehavioral side-effects. In the following, we provide recommendations for programs of research aimed at identifying sources of heterogeneity in women's experiences with HC. First, we review research demonstrating person- and prescription- based heterogeneity in women's psychobehavioral responses to HCs. Next, we identify several promising person- and prescription- based sources of this heterogeneity that warrant future research. We close with a discussion of research approaches that are particularly well-suited to address the research questions raised in article. Together, this review provides researchers with several promising research pathways to help support the development of a precision medicine approach to HC treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Tauopathies, such as Alzheimer's disease, are characterized by the misfolding and progressive accumulation of the microtubule associated protein tau. Chaperones, tasked with maintaining protein homeostasis, can become imbalanced with age and contribute to the progression of neurodegenerative disease. Cyclophilins are a promising pool of underinvestigated chaperones with peptidyl-prolyl isomerase activity that may play protective roles in regulating tau aggregation. Using a Thioflavin T fluorescence-based assay to monitor in vitro tau aggregation, all eight cyclophilins, which include PPIA to PPIH prevent tau aggregation, with PPIB, PPIC, PPID, and PPIH showing the greatest inhibition. The low thermal stability of PPID and the strong heparin binding of PPIB undermines the simplistic interpretation of reduced tau aggregation. In a cellular model of tau accumulation, all cyclophilins, except PPID and PPIH, reduce insoluble tau. PPIB, PPIC, PPIE, and PPIF also reduce soluble tau levels with PPIC exclusively protecting cells from tau seeding. Overall, this study demonstrates cyclophilins prevent tau fibril formation and many reduce cellular insoluble tau accumulation with PPIC having the greatest potential as a molecular tool to mitigate tau seeding and accumulation., (© 2022 The Protein Society.)

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., (© 2022. The Author(s).)

DNA polymerase ζ (pol ζ) plays a central role in replicating damaged genomic DNA. When DNA synthesis stalls at a lesion, it participates in translesion DNA synthesis (TLS), which helps replication proceed. TLS prevents cell death at the expense of new mutations. The current model indicates that pol ζ-dependent TLS events are mediated by Pol31/Pol32 pol ζ subunits, which are shared with replicative polymerase pol δ. Surprisingly, we found that the mutant rev3- Δ C in yeast, which lacks the C-terminal domain (CTD) of the catalytic subunit of pol ζ and, thus, the platform for interaction with Pol31/Pol32, retains most pol ζ functions. To understand the underlying mechanisms, we studied TLS in normal templates or templates with abasic sites in vitro in primer extension reactions with purified four-subunit pol ζ versus pol ζ with Rev3-ΔC. We also examined the specificity of ultraviolet radiation (UVR)-induced mutagenesis in the rev3- Δ C strains. We found that the absence of Rev3 CTD reduces activity levels, but does not alter the basic biochemical properties of pol ζ, and alters the mutation spectrum only at high doses of UVR, alluding to the existence of mechanisms of recruitment of pol ζ to UVR-damaged sites independent of the interaction of Pol31/Pol32 with the CTD of Rev3.

Introduction: The UK Overseas Territories (UKOTs) are semi-autonomous jurisdictions that face distinctive challenges in implementing tobacco control and protecting policy from industry influence. They are not eligible to become independent parties of the WHO Framework Convention on Tobacco Control (FCTC), although they can apply for treaty extension under the UK's ratification. This study explores the relevance of the FCTC-particularly Article 5.3-for tobacco control governance across a sample of UKOTs., Methods: From March to May 2019, we interviewed 32 stakeholders across four territories (Anguilla, Bermuda, Cayman Islands, St Helena) at diverse stages in implementing key FCTC measures. Thematic qualitative analysis explored awareness and perceptions in relation to tobacco control., Results: Interviewees' accounts highlight the complexity of protecting health policy from industry influence in a context where the 'tobacco industry' covers a diverse range of actors. Despite not being formally covered by the FCTC, several health officials spoke about the strategic value of invoking Article 5.3 in the context of tensions with economic priorities. Nevertheless, effective tobacco control governance is complicated by territories' reliance on local businesses-including tourism-and close social connections that occasionally blur the lines between private and public spheres., Conclusions: The UKOTs share many characteristics with other small island jurisdictions, creating distinctive challenges for advancing tobacco control and protecting policy from industry interference. Despite their complex status in relation to WHO and its architecture, these territories benefit from the norms embedded in the FCTC and the systems that support its implementation., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Much research indicates that exposure to early life adversity (ELA) predicts chronic inflammatory activity, increasing one's risk of developing diseases of aging later in life. Despite its costs, researchers have proposed that chronic inflammation may be favored in this context because it would help promote immunological vigilance in environments with an elevated risk of infection and injury. Although intuitively appealing, the assumption that exaggerated inflammatory activity predicts favorable immunological outcomes among those exposed to ELA has not been tested. Here, we seek to address this gap, examining the links between exposure to ELA, inflammation, and immune function. Consistent with others' work, results revealed that those from low socioeconomic status (SES) childhood environments exhibited exaggerated unstimulated inflammatory activity relative to what was observed among those from higher SES childhood environments. Further, results revealed that - although levels of inflammation predicted the magnitude of immunological responses in those from higher SES backgrounds - for those who grew up in low SES environments, higher levels of inflammation were unrelated to the magnitude of immunological responses. Results suggest that exaggerated inflammatory activity in the context of ELA may not predict improved ability to manage acute immunological threats.

One of the best studied global "hot spots" for ecological mercury (Hg) contamination is south Florida (USA), where elevated Hg concentrations in environmental media and regional wildlife were first described over thirty years ago. While Hg contamination has lessened in this region, it is still critical to monitor Hg uptake and potential risks in south Florida wildlife, especially in marine-associated birds, which are known to accumulate potentially toxic Hg levels. In this study, total Hg (THg) concentrations were measured in liver, kidney, muscle, and feathers of 101 individuals from seven species of south Florida birds: brown pelican Pelecanus occidentalis, double-crested cormorant Phalacrocorax auratus, herring gull Larus argentatus, laughing gull Leucophaeus atricilla, northern gannet Morus bassanus, royal tern Thalasseus maximus, and osprey Pandion halietus. A sizeable proportion of individuals (> 40%) were found to contain THg concentrations in internal tissues that exceeded estimated toxicity thresholds for Hg-related effects. Certain species, especially osprey, were found to exhibit a higher rate of threshold exceedances than others and should continue to be monitored for Hg-related effects in future studies. Feather THg concentrations exhibited a lower rate of toxicity threshold exceedances (12%) and were not significantly correlated with those in internal tissues in most cases, suggesting that they may not be well suited for monitoring Hg exposure in these species unless sources of data variation can be better understood. The results of the present study contribute significantly to our understanding of trends in Hg accumulation and Hg-related health risks in south Florida marine-associated birds., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Autophagy is a cellular degradation pathway essential for neuronal health and function. Autophagosome biogenesis occurs at synapses, is locally regulated, and increases in response to neuronal activity. The mechanisms that couple autophagosome biogenesis to synaptic activity remain unknown. In this study, we determine that trafficking of ATG-9, the only transmembrane protein in the core autophagy pathway, links the synaptic vesicle cycle with autophagy. ATG-9-positive vesicles in C. elegans are generated from the trans-Golgi network via AP-3-dependent budding and delivered to presynaptic sites. At presynaptic sites, ATG-9 undergoes exo-endocytosis in an activity-dependent manner. Mutations that disrupt endocytosis, including a lesion in synaptojanin 1 associated with Parkinson's disease, result in abnormal ATG-9 accumulation at clathrin-rich synaptic foci and defects in activity-induced presynaptic autophagy. Our findings uncover regulated key steps of ATG-9 trafficking at presynaptic sites and provide evidence that ATG-9 exo-endocytosis couples autophagosome biogenesis at presynaptic sites with the activity-dependent synaptic vesicle cycle., Competing Interests: Declaration of interests P.D.C. is a member of the scientific advisory board of Casma Therapeutics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia 1-3 , two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43 4,5 . Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies., (© 2022. The Author(s).)

It has long been hypothesized that attractiveness provides a cue to a target's health and immunocompetence. However, much of the research testing this hypothesis has relied on a small number of indirect proxies of immune function, and the results of this research have been mixed. Here, we build on this past research, examining the relationship between target attractiveness and (i) self-reported health, (ii) in vivo measures of inflammation and white blood cell count/composition, and (iii) in vitro tests of targets' immune function, including (c 1 ) leucocyte proliferation in response to immunological stimulants, (c 2 ) phagocytosis of Escherichia coli bioparticles, (c 3 ) NK cell-mediated lysis of target tumour cells, and (c 4 ) Staphylococcus aureus growth in isolated plasma. Results revealed multiple, sometimes sex-differentiated, relationships between targets' immune function and others' perceptions of their attractiveness. Together, this work suggests complex, often sex-differentiated relationships between immune function, health, and attractiveness.

In Western dual-educated, male-female marriages, women who divorce face greater burdens because of decreased income and primary or sole responsibility for caring for children than men who divorce. Why, then, do these women initiate divorce more and fare better psychologically after a divorce than men? Here, we articulate an evolutionary mismatch perspective, informed by key findings in relationship science. We argue that mismatches between women's evolved preferences and configurations of modern marriage often clash, producing dissatisfaction. Women's unprecedented career ascendance also affords women ever more freedom to leave. We discuss pressures from social expectations for men and women that contribute to or compound these vulnerabilities. We conclude with key questions for future research, which can contribute to strategies for mitigating relationship dissatisfaction and the profound loss and pain that results from divorce., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Decades of research finds associations between personality traits and health. In recent years, it has become clear that the activities of the immune system play a key role in linking these variables. In the current work, we add to this research by exploring the relationship between Big Five personality traits and (Study 1) polymorphisms known to impact cytokine release and (Study 2) immunological parameters measured in vivo (differential white blood cell counts, plasma proinflammatory cytokine levels) and in vitro (proinflammatory cytokine release by peripheral blood mononuclear cells, Staphylococcus aureus growth in plasma). Results provide insights into potential mechanistic drivers of the link between personality and immune function and the possibility that, in some cases, relationships between personality and immune function may be sex differentiated.

A substantial body of research describes the distribution, causes and potential reduction of health inequalities, yet little scholarship examines public understandings of these inequalities. Existing work is dominated by small-scale, qualitative studies of the experiences of specific communities. As a result, we know very little about what broader publics think about health inequalities; and even less about public views of potential policy responses. This is an important gap since previous research shows many researchers and policymakers believe proposals for 'upstream' policies are unlikely to attract sufficient public support to be viable. This mixed methods study combined a nationally representative survey with three two-day citizens' juries exploring public views of health inequalities and potential policy responses in three UK cities (Glasgow, Manchester and Liverpool) in July 2016. Comparing public opinion elicited via a survey to public reasoning generated through deliberative processes offers insight into the formation of public views. The results challenge perceptions that there is a lack of public support for upstream, macro-level policy proposals and instead demonstrate support for proposals aiming to tackle health inequalities via improvements to living and working conditions, with more limited support for proposals targeting individual behavioural change. At the same time, some macro-economic proposals, notably those involving tax increases, proved controversial among study participants and results varied markedly by data source. Our analysis suggests that this results from three intersecting factors: a resistance to ideas viewed as disempowering (which include, fundamentally, the idea that health inequalities exist); the prevalence of individualising and fatalistic discourses, which inform resistance to diverse policy proposals (but especially those that are more 'upstream', macro-level proposals); and a lack of trust in (local and national) government. This suggests that efforts to enhance public support for evidence-informed policy responses to health inequalities may struggle unless these broader challenges are also addressed., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Recombinant antibodies with well-characterized epitopes and known conformational specificities are critical reagents to support robust interpretation and reproducibility of immunoassays across biomedical research. For myocilin, a protein prone to misfolding that is associated with glaucoma and an emerging player in other human diseases, currently available antibodies are unable to differentiate among the numerous disease-associated protein states. This fundamentally constrains efforts to understand the connection between myocilin structure, function, and disease. To address this concern, we used protein engineering methods to develop new recombinant antibodies that detect the N-terminal leucine zipper structural domain of myocilin and that are cross-reactive for human and mouse myocilin. After harvesting spleens from immunized mice and in vitro library panning, we identified two antibodies, 2A4 and 1G12. 2A4 specifically recognizes a folded epitope while 1G12 recognizes a range of conformations. We matured antibody 2A4 for improved biophysical properties, resulting in variant 2H2. In a human IgG1 format, 2A4, 1G12, and 2H2 immunoprecipitate full-length folded myocilin present in the spent media of human trabecular meshwork (TM) cells, and 2H2 can visualize myocilin in fixed human TM cells using fluorescence microscopy. These new antibodies should find broad application in glaucoma and other research across multiple species platforms., Competing Interests: Conflict of interest A. C. P.-O., A. N. Q., L. R. A., S. E. H., J. A. M., and R. L. L. are coinventors of US Provisional Patent 62/776,799., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Vibrio cholerae is an aquatic Gram-negative bacterium that causes severe diarrheal cholera disease when ingested by humans. To eliminate competitor cells in both the external environment and inside hosts, V. cholerae uses the type VI secretion system (T6SS). The T6SS is a macromolecular contact-dependent weapon employed by many Gram-negative bacteria to deliver cytotoxic proteins into adjacent cells. In addition to canonical T6SS gene clusters encoded by all sequenced V. cholerae isolates, strain BGT49 encodes another locus, which we named auxiliary (Aux) cluster 4. The Aux 4 cluster is located on a mobile genetic element and can be used by killer cells to eliminate both V. cholerae and Escherichia coli cells in a T6SS-dependent manner. A putative toxin encoded in the cluster, which we name TpeV ( t ype VI p ermeabilizing e ffector V ibrio ), shares no homology to known proteins and does not contain motifs or domains indicative of function. Ectopic expression of TpeV in the periplasm of E. coli permeabilizes cells and disrupts the membrane potential. Using confocal microscopy, we confirm that susceptible target cells become permeabilized when competed with killer cells harboring the Aux 4 cluster. We also determine that tpiV , the gene located immediately downstream of tpeV , encodes an immunity protein that neutralizes the toxicity of TpeV. Finally, we show that TpeV homologs are broadly distributed across important human, animal, and plant pathogens and are localized in proximity to other T6SS genes. Our results suggest that TpeV is a toxin that belongs to a large family of T6SS proteins. IMPORTANCE Bacteria live in polymicrobial communities where competition for resources and space is essential for survival. Proteobacteria use the T6SS to eliminate neighboring cells and cause disease. However, the mechanisms by which many T6SS toxins kill or inhibit susceptible target cells are poorly understood. The sequence of the TpeV toxin that we describe here is unlike any previously described protein. We demonstrate that it has antimicrobial activity by permeabilizing cells, eliminating membrane potentials, and causing severe cytotoxicity. TpeV homologs are found near known T6SS genes in human, animal, and plant bacterial pathogens, indicating that the toxin is a representative member of a broadly distributed protein family. We propose that TpeV-like toxins contribute to the fitness of many bacteria. Finally, since antibiotic resistance is a critical global health threat, the discovery of new antimicrobial mechanisms could lead to the development of new treatments against resistant strains.