Longitudinal associations between women's cycle characteristics and sexual motivation using Flo cycle tracking data.

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 (ßs: - 0.10 to - 0.06, ps < 0.001), but (d) changes in sexual motivation did not reliably precede changes in cycle length (ßs: - 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 (ß = - 0.06, p < 0.001), insomnia (ß = - 0.03, p < 0.001), and food cravings (ß = - 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.

Longitudinal changes in sexual desire and attraction among women who started using the Natural Cycles app.

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.

TDP-43 loss induces extensive cryptic polyadenylation in ALS/FTD.

Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 is the hallmark of ALS, occurring in over 97% of cases. A key consequence of TDP-43 nuclear loss is the de-repression of cryptic exons. Whilst TDP-43 regulated cryptic splicing is increasingly well catalogued, cryptic alternative polyadenylation (APA) events, which define the 3' end of last exons, have been largely overlooked, especially when not associated with novel upstream splice junctions. We developed a novel bioinformatic approach to reliably identify distinct APA event types: alternative last exons (ALE), 3'UTR extensions (3'Ext) and intronic polyadenylation (IPA) events. We identified novel neuronal cryptic APA sites induced by TDP-43 loss of function by systematically applying our pipeline to a compendium of publicly available and in house datasets. We find that TDP-43 binding sites and target motifs are enriched at these cryptic events and that TDP-43 can have both repressive and enhancing action on APA. Importantly, all categories of cryptic APA can also be identified in ALS and FTD post mortem brain regions with TDP-43 proteinopathy underlining their potential disease relevance. RNA-seq and Ribo-seq analyses indicate that distinct cryptic APA categories have different downstream effects on transcript and translation. Intriguingly, cryptic 3'Exts occur in multiple transcription factors, such as ELK1, SIX3, and TLX1, and lead to an increase in wild-type protein levels and function. Finally, we show that an increase in RNA stability leading to a higher cytoplasmic localisation underlies these observations. In summary, we demonstrate that TDP-43 nuclear depletion induces a novel category of cryptic RNA processing events and we expand the palette of TDP-43 loss consequences by showing this can also lead to an increase in normal protein translation.

Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

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.

Association Between Clinical Encounter Frequency and HIV-Related Stigma Among Newly-Diagnosed People Living with HIV in Rwanda.

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.

Hormonal contraceptive use is associated with differences in women's inflammatory and psychological reactivity to an acute social stressor.

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 (Mage = 19.31, SDage = 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.

Applying a One Health lens to understanding the impact of climate and environmental change on healthcare-associated infections.

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.

The active zone protein Clarinet regulates synaptic sorting of ATG-9 and presynaptic autophagy.

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.

Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

Functional loss of TDP-43, an RNA-binding protein genetically and pathologically linked to ALS and FTD, leads to inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. However, the possibility of de novo protein synthesis from cryptic exon transcripts has not been explored. Here, we show that mRNA transcripts harboring cryptic exons generate de novo proteins both in TDP-43 deficient cellular models and in disease. Using coordinated transcriptomic and proteomic studies of TDP-43 depleted iPSC-derived neurons, we identified numerous peptides that mapped to cryptic exons. Cryptic exons identified in iPSC models were highly predictive of cryptic exons expressed in brains of patients with TDP-43 proteinopathy, including cryptic transcripts that generated de novo proteins. We discovered that inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Finally, we showed that these de novo peptides were present in CSF from patients with ALS. The demonstration of cryptic exon translation suggests new mechanisms for ALS pathophysiology downstream of TDP-43 dysfunction and may provide a strategy for novel biomarker development.

A Scoping Review of Health Care Faculty Mentorship Programs in Academia: Implications for Program Design, Implementation, and Outcome Evaluation.

INTRODUCTION: Formal mentoring programs have direct benefits for academic health care institutions, but it is unclear whether program designs use recommended components and whether outcomes are being captured and evaluated appropriately. The goal of this scoping review is to address these questions. METHODS: We completed a literature review using a comprehensive search in SCOPUS and PubMed (1998-2019), a direct solicitation for unpublished programs, and hand-searched key references, while targeting mentor programs in the United States, Puerto Rico, and Canada. After three rounds of screening, team members independently reviewed and extracted assigned articles for 40 design data items into a comprehensive database. RESULTS: Fifty-eight distinct mentoring programs were represented in the data set. The team members clarified specific mentor roles to assist the analysis. The analysis identified mentoring program characteristics that were properly implemented, including identifying program goals, specifying the target learners, and performing a needs assessment. The analysis also identified areas for improvement, including consistent use of models/frameworks for program design, implementation of mentor preparation, consistent reporting of objective outcomes and career satisfaction outcomes, engagement of program evaluation methods, increasing frequency of reports as programs as they mature, addressing the needs of specific faculty groups (eg, women and minority faculty), and providing analyses of program cost-effectiveness in relation to resource allocation (return on investment). CONCLUSION: The review found that several mentor program design, implementation, outcome, and evaluation components are poorly aligned with recommendations, and content for URM and women faculty members is underrepresented. The review should provide academic leadership information to improve these discrepancies.

Moving beyond the mean: Promising research pathways to support a precision medicine approach to hormonal contraception.

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.

Design of a Novel Orthodontic Appliance to Prevent Pedicle Trauma in Patients Undergoing Double-Opposing Buccal Flaps for Palatal Lengthening.

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.

'Choice should be made through educated decisions not regressive dictates': discursive framings of a proposed 'sugar tax' in Bermuda: analysis of submissions to a government consultation.

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.

DNA Polymerase ζ without the C-Terminus of Catalytic Subunit Rev3 Retains Characteristic Activity, but Alters Mutation Specificity of Ultraviolet Radiation in Yeast.

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-ΔC 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-ΔC 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.

The Nature and Evolution of the Mentoring Relationship in Academic Health Centers.

Mentoring has a long tradition in academic health centers, and from an institutional perspective can positively impact retention, wellness, promotion success, work satisfaction, and more. On the individual level, mentorship can provide professional growth and personal satisfaction for both participants. However, mentors may struggle with how to build their mentorship skills, navigating challenges with mentees over time, or if/how/when to conclude a mentor-mentee relationship. Mentees may not understand how to find a mentor, what the nature of that relationship is, or what their role is (what characterizes a "good" mentee). As important as mentorship is, it can be challenging for both to find and maintain a high-quality mentor-mentee relationship. This article reviews the qualities that are most critical in developing a successful mentoring relationship, the longitudinal nature of this relationship, common problems that arise, and the potential rewards that exist for each person involved in the relationship.

Accumulation of the Toxic Metal Mercury in Multiple Tissues of Marine-Associated Birds from South Florida.

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.

From silos to policy coherence: tobacco control, unhealthy commodity industries and the commercial determinants of health.

Tobacco control has achieved remarkable successes, underpinned by the distinctive norms codified in Article 5.3 of the WHO Framework Convention on Tobacco Control. Tobacco control's experience in managing conflicts of interest is increasingly recognised as relevant for addressing other non-communicable disease epidemics. At the same time, the wider environmental and social harms of tobacco-and other unhealthy commodity industries-underline the potential for enhanced strategic collaboration across health, development and environmental agendas. Such collaboration is increasingly necessary to address key challenges shared across tobacco control and related policy spheres, including the extent to which the harms of tobacco (and other unhealthy commodities) are underpinned by economic and social inequities. Here we demonstrate the relevance of a commercial determinants of health perspective, both for advancing tobacco control and for linking it with health and development more broadly. This perspective is already evident in many areas of research, policy and advocacy, where innovative approaches support the development of closer links with actors in related fields. We draw on the concepts of policy coordination, coherence and integration to show how tobacco control can advance key strategic goals via information sharing, complementary approaches to common problems and collective action with other related movements. Embrace of a commercial determinants perspective will help in building on tobacco control's successes and reorienting strategies in other sectors to more effectively manage health risks and promote sustainable development.

TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A.

Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1-3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. 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.

More than just a pretty face? The relationship between immune function and perceived facial attractiveness.

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 (c1) leucocyte proliferation in response to immunological stimulants, (c2) phagocytosis of Escherichia coli bioparticles, (c3) NK cell-mediated lysis of target tumour cells, and (c4) 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.