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Background and Aims: The Moral Incongruence Model of Pornography Use proposes that pornography-use-related problems may be present due to problematic pornography use (PPU) and/or moral disapproval (MD) of pornography use. Despite some supporting empirical evidence, no study has tested the presence of different pornography-use profiles based on individuals' behavioral dysregulation (i.e., PPU) and moral values concerning pornography use. The generalizability of previous findings to diverse populations has also been limited given the scarcity of studies conducted outside of Western countries., Methods: Using data from the International Sex Survey (42 countries, N = 66,994; Mage = 32.16 years, SD = 12.27), we conducted latent profile analysis to identify pornography-use profiles based on individuals' frequency of use, MD, and PPU. The profiles were compared along a wide range of pornography-use-related, sexuality-related, and psychological correlates., Results: Six pornography-use profiles were identified, including two increased risk groups (i.e., Increased risk of PPU without MD and Increased risk of PPU with some MD). Several factors differentiated between the increased risk vs. no/low risk profiles (e.g., relatedness satisfaction) as well as between the two increased risk profiles (e.g., religiosity). Apart from behavioral dysregulation, moral values concerning pornography use played an important role in distinguishing pornography-use profiles and demonstrated the importance of inquiring about MD when working with individuals with pornography-use-related problems., Conclusion: Findings also support recent calls for better-integrated sex therapy and sexual medicine perspectives into pornography-use-related problems research and care.

Background and Aims: Despite a growing body of research on pornography use among women, there is a lack of understanding of the problematic versus non-problematic nature. The current study aimed to investigate the relationship between women's motivations for pornography use and sexual wellbeing using a cross-sectional, self-report survey design among participants from 42 countries., Methods: The total sample included 82,243 participants, of whom 46,874 (57.0%) identified as women and were analyzed. The participants' age averaged at M = 29.67 years, with a standard deviation of SD = 10.11. Participants were asked to complete a questionnaire assessing their motivations for pornography use, as well as measures of sexual functioning, sexual desire, and sexual satisfaction., Results: Study results suggest that across cultures, women's motivations for pornography use are associated with their sexual wellbeing. Specifically, when women reported using pornography for their own pleasure or sexual curiosity, it was associated with fewer sexual functioning problems and higher sexual desire. Conversely, when women reported using pornography due to a lack of sexual satisfaction in their relationships, it was associated with more sexual functioning problems., Discussion and Conclusions: These findings highlight the need to consider the multifaceted nature of pornography use among women, including the usage motives, to fully understand associations with sexual wellbeing. Additionally, the study emphasizes the importance of conducting further research utilizing longitudinal designs, to establish the directionality between pornography use motivations and sexual wellbeing among women.

During transport through the oviduct, sperm interact with epithelial cells by attaching to specific glycans, a mechanism believed to select sperm and prolong their viability. An in vitro model of sperm-oviduct interactions was developed, consisting of a glass surface (either a slide or a coverslip) to which an oviduct glycan (sulfated Lewis X trisaccharide; suLe X ) is coupled. The ability of porcine sperm to attach to suLe X -surfaces and detach in response to progesterone and mature cumulus-oocyte complexes (COCs) was validated. The suLe X -coverslip was adapted for in vitro fertilization (IVF), termed glycan-IVF, by allowing porcine sperm to first bind suLe X before transferring mature COCs. The glycan-IVF method produced a percentage of fertilized oocytes comparable to that of conventional IVF (75.1 vs. 72.0%). Finally, the ability of the suLe X -coverslip to maintain sperm fertilizing ability over time was assessed. After 24 h of incubation, fertilization by sperm bound to the suLe X -coverslip was sustained, compared to sperm with unmodified coverslips (12.0 vs. 1.0%, p < 0.05). Furthermore, the percentage of polyspermic zygotes was reduced in the suLe X -coverslip method (17.7 vs. 41.3%, p < 0.05). This study validated an in vitro model for studying sperm-oviduct interactions, with potential applications in assisted reproductive technologies., Competing Interests: Declarations. Competing interests: S.S.-H. is currently employed by Epivara, Inc. L.V., N.B., and D.M. declare no competing interests., (© 2025. The Author(s).)

X-ray crystal diffraction has provided atomic-level structural information on biological macromolecules. Data quality determines the reliability of structural models. In most cases, multiple data sets are available from different crystals and/or collected with different experimental settings. Reliable metrics are critical to rank and select the data set with the highest quality. Many measures have been created or modified for data quality evaluation. However, some are duplicate in functionality, and some are likely misused due to misunderstanding, which causes confusion or problems, especially at synchrotron beamlines where experiments proceed quickly. In this work, these measures are studied through both theoretical analysis and experimental data with various characteristics, which demonstrated that: 1). {Rmerg, Rmeas, Rpim, CC1/2} all measure the equivalence of reflections, and the low-shell values of these metrics can be used as reliable indicators for correctness (or trueness) of Laue symmetry; 2). High-shell I / σ I is a reliable and better indicator to select resolution cutoff while the overall value measures the overall strength of the data.

Specificity of the ubiquitin-proteasome system depends on E3 ligase-substrate interactions. Many such pairings depend on E3 ligases binding to peptide-like sequences - termed N- or C-degrons - at the termini of substrates. However, our knowledge of structural features distinguishing closely related C-degron substrate-E3 pairings is limited. Here, by systematically comparing ubiquitylation activities towards a suite of common model substrates, and defining interactions by biochemistry, crystallography, and cryo-EM, we reveal principles of C-degron recognition across the KLHDCX family of Cullin-RING ligases (CRLs). First, a motif common across these E3 ligases anchors a substrate's C-terminus. However, distinct locations of this C-terminus anchor motif in different blades of the KLHDC2, KLHDC3, and KLHDC10 β-propellers establishes distinct relative positioning and molecular environments for substrate C-termini. Second, our structural data show KLHDC3 has a pre-formed pocket establishing preference for an Arg or Gln preceding a C-terminal Gly, whereas conformational malleability contributes to KLHDC10's recognition of varying features adjacent to substrate C-termini. Finally, additional non-consensus interactions, mediated by C-degron binding grooves and/or by distal propeller surfaces and substrate globular domains, can substantially impact substrate binding and ubiquitylatability. Overall, the data reveal combinatorial mechanisms determining specificity and plasticity of substrate recognition by KLDCX-family C-degron E3 ligases., Competing Interests: Competing interests D.C.S. and B.A.S. are co-inventors of intellectual property that is unrelated to this work (DCN1 inhibitors licensed to Cinsano). J.W.H. is a founder and consultant for Caraway Therapeutics and is a scientific advisory board member for Lyterian Therapeutics. SJE is a founder of, and holds equity in TScan Therapeutics and Immune ID. S.J.E. is also founder of MAZE Therapeutics, and Mirimus and serves on the scientific advisory board of TSCAN Therapeutics, and MAZE Therapeutics. In accordance with Partners HealthCare’s conflict of interest policies, the Partners Office for Interactions with Industry has reviewed SJE’s financial interest in TSCAN and determined that it creates no significant risk to the welfare of participants in this study or to the integrity of this research. B.A.S. is a member of the scientific advisory boards of Biotheryx and Proxygen. The remaining authors declare no competing interests., (© 2024. The Author(s).)

PROTAC® (proteolysis-targeting chimera) molecules induce proximity between an E3 ligase and protein-of-interest (POI) to target the POI for ubiquitin-mediated degradation. Cooperative E3-PROTAC-POI complexes have potential to achieve neo-substrate selectivity beyond that established by POI binding to the ligand alone. Here, we extend the collection of ubiquitin ligases employable for cooperative ternary complex formation to include the C-degron E3 KLHDC2. Ligands were identified that engage the C-degron binding site in KLHDC2, subjected to structure-based improvement, and linked to JQ1 for BET-family neo-substrate recruitment. Consideration of the exit vector emanating from the ligand engaged in KLHDC2's U-shaped degron-binding pocket enabled generation of SJ46421, which drives formation of a remarkably cooperative, paralog-selective ternary complex with BRD3 BD2 . Meanwhile, screening pro-drug variants enabled surmounting cell permeability limitations imposed by acidic moieties resembling the KLHDC2-binding C-degron. Selectivity for BRD3 compared to other BET-family members is further manifested in ubiquitylation in vitro, and prodrug version SJ46420-mediated degradation in cells. Selectivity is also achieved for the ubiquitin ligase, overcoming E3 auto-inhibition to engage KLHDC2, but not the related KLHDC1, KLHDC3, or KLHDC10 E3s. In sum, our study establishes neo-substrate-specific targeted protein degradation via KLHDC2, and provides a framework for developing selective PROTAC protein degraders employing C-degron E3 ligases., (© 2024. The Author(s).)

One of the practical contributions of epidemiology studies is to inform risk assessment and management to protect public health. However, there is a perception among some that environmental and occupational epidemiology is falling short of satisfying the needs of risk assessors. The specific reasons for this are not clearly understood. To help identify the points of dissatisfaction and possible areas for mutual learning, we conducted a survey of risk assessors, seeking their opinions of epidemiology research. We present a few quantitative measures and a thematic analysis of responses to open-ended questions. Survey results suggest that some risk assessors (with some adamant exceptions) believe that epidemiology has great potential to contribute to risk assessment but can be deficient in many ways. For example, respondents identified the lack of full disclosure of methods, deficiencies in exposure assessment, the absence of comprehensive uncertainty analyses, and the failure to investigate or explore thresholds of effects as some of the common shortcomings. These could be straightforward to address. Respondents also brought up a wide collection of more complicated and subtle concerns that could lead to further improvement of useful results. We identify areas where mutually-educating interdisciplinary dialogue seems particularly promising. Epidemiology research is expensive, and risk management decisions even more so; therefore, it is desirable for the risk assessment and epidemiologic communities to work toward making epidemiologic research more useful for informing decisions., Competing Interests: The authors declare no financial conflicts of interest other than their employment relationships with companies that might have some unidentified goals that conflict with the goals of this work. IB and CVP disclose activism on behalf of better bias analyses and other improvements in the conduct of epidemiology, belief in existence of thresholds in biology, and sincere desire to make risk assessment more quantitative. While there is no apparent way that the financing of this project would create any conflict of interest regarding the project goals, design, or analysis, we also disclose that CVP was contracted for this project by HESI, IB subsumed it into his academic duties, SD worked on it as part of her employment at HESI, and the other authors volunteered their time., (© 2024 The Authors.)

Background: The aim of this study was to examine the effect of pressure training on the performance of semi-professional female rugby league athletes., Methods: Using a within-subjects design, 16 female athletes (19.9 ± 3.4 years) performed a passing accuracy task under three conditions; (1) a control condition; (2) a physiological fatigue condition; and (3) a threat of consequence condition. Passing performance, perceived pressure, rate of perceived exertion (RPE), and self-confidence were assessed., Results: A significant main effect of conditions was found for rate of perceived exertion ( p < 0.001), self-confidence ( p < 0.028), and perceived pressure ( p = 0.011). There was no main effect of condition on passing performance. Post hoc comparisons revealed that RPE was significantly higher in the physiological fatigue condition when compared to the control ( p = 0.009) and threat of consequence conditions ( p < 0.001). Perceived pressure was significantly higher in the threat of consequence condition compared to the control condition ( p = 0.037)., Conclusions: The main findings of this study are that (1) passing performance was not impacted by pressure training conditions, and (2) threats of consequences are an effective manipulation to generate pressure in female semi-professional rugby league players. These results offer nuanced insights into the impact of pressure generation in training environments for female semi-professional rugby league athletes.

Nuclear receptors are ligand-activated transcription factors that can often be useful drug targets. Unfortunately, ligand promiscuity leads to two-thirds of receptors remaining clinically untargeted. PXR is a nuclear receptor that can be activated by diverse compounds to elevate metabolism, negatively impacting drug efficacy and safety. This presents a barrier to drug development because compounds designed to target other proteins must avoid PXR activation while retaining potency for the desired target. This problem could be avoided by using PXR antagonists, but these compounds are rare, and their molecular mechanisms remain unknown. Here, we report structurally related PXR-selective agonists and antagonists and their corresponding co-crystal structures to describe mechanisms of antagonism and selectivity. Structural and computational approaches show that antagonists induce PXR conformational changes incompatible with transcriptional coactivator recruitment. These results guide the design of compounds with predictable agonist/antagonist activities and bolster efforts to generate antagonists to prevent PXR activation interfering with other drugs., (© 2024. The Author(s).)

Background: Sleep is a critical component of recovery, but it can be disrupted following prolonged endurance exercise. The objective of this study was to examine the capacity of male and female professional cyclists to recover between daily race stages while competing in the 2022 Tour de France and the 2022 Tour de France Femmes, respectively. The 17 participating cyclists (8 males from a single team and 9 females from two teams) wore a fitness tracker (WHOOP 4.0) to capture recovery metrics related to night-time sleep and autonomic activity for the entirety of the events and for 7 days of baseline before the events. The primary analyses tested for a main effect of 'stage classification'-i.e., rest, flat, hilly, mountain or time trial for males and flat, hilly or mountain for females-on the various recovery metrics., Results: During baseline, total sleep time was 7.2 ± 0.3 h for male cyclists (mean ± 95% confidence interval) and 7.7 ± 0.3 h for female cyclists, sleep efficiency was 87.0 ± 4.4% for males and 88.8 ± 2.6% for females, resting HR was 41.8 ± 4.5 beats·min -1 for males and 45.8 ± 4.9 beats·min -1 for females, and heart rate variability during sleep was 108.5 ± 17.0 ms for males and 119.8 ± 26.4 ms for females. During their respective events, total sleep time was 7.2 ± 0.1 h for males and 7.5 ± 0.3 h for females, sleep efficiency was 86.4 ± 1.2% for males and 89.6 ± 1.2% for females, resting HR was 44.5 ± 1.2 beats·min -1 for males and 50.2 ± 2.0 beats·min -1 for females, and heart rate variability during sleep was 99.1 ± 4.2 ms for males and 114.3 ± 11.2 ms for females. For male cyclists, there was a main effect of 'stage classification' on recovery, such that heart rate variability during sleep was lowest after mountain stages. For female cyclists, there was a main effect of 'stage classification' on recovery, such that the percentage of light sleep (i.e., lower-quality sleep) was highest after mountain stages., Conclusions: Some aspects of recovery were compromised after the most demanding days of racing, i.e., mountain stages. Overall however, the cyclists obtained a reasonable amount of good-quality sleep while competing in these physiologically demanding endurance events. This study demonstrates that it is now feasible to assess recovery in professional athletes during multiple-day endurance events using validated fitness trackers., (© 2024. The Author(s).)

Background: The three-item Sexual Distress Scale (SDS-3) has been frequently used to assess distress related to sexuality in public health surveys and research on sexual wellbeing. However, its psychometric properties and measurement invariance across cultural, gender and sexual subgroups have not yet been examined. This multinational study aimed to validate the SDS-3 and test its psychometric properties, including measurement invariance across language, country, gender identity, and sexual orientation groups., Methods: We used global survey data from 82,243 individuals (Mean age =32.39 years; 40.3 % men, 57.0 % women, 2.8 % non-binary, and 0.6 % other genders) participating in the International Sexual Survey (ISS; https://internationalsexsurvey.org/) across 42 countries and 26 languages. Participants completed the SDS-3, as well as questions regarding sociodemographic characteristics, including gender identity and sexual orientation., Results: Confirmatory factor analysis (CFA) supported a unidimensional factor structure for the SDS-3, and multi-group CFA (MGCFA) suggested that this factor structure was invariant across countries, languages, gender identities, and sexual orientations. Cronbach's α for the unidimensional score was 0.83 (range between 0.76 and 0.89), and McDonald's ω was 0.84 (range between 0.76 and 0.90). Participants who did not experience sexual problems had significantly lower SDS-3 total scores ( M = 2.99; SD =2.54) compared to those who reported sexual problems ( M = 5.60; SD =3.00), with a large effect size (Cohen's d = 1.01 [95 % CI=-1.03, -0.98]; p < 0.001)., Conclusion: The SDS-3 has a unidimensional factor structure and appears to be valid and reliable for measuring sexual distress among individuals from different countries, gender identities, and sexual orientations., Competing Interests: The authors declare no conflict of interest with the content of this manuscript. SWK discloses that he has received funding from the International Center for Responsible Gaming, MGM Resorts International, Center for the Application of Substance Abuse Technologies, Taylor Francis, Springer Nature, The Nevada Problem Gambling Project, Sports Betting Alliance, and Kindbridge Research Institute. Dr. Potenza discloses that he has consulted for and advised Game Day Data, Addiction Policy Forum, AXA, Idorsia, Baria-Tek, and Opiant Therapeutics; been involved in a patent application involving Novartis and Yale; received research support from the Mohegan Sun Casino, Children and Screens and the Connecticut Council on Problem Gambling; consulted for or advised legal and gambling entities on issues related to impulse control, internet use and addictive behaviours; performed grant reviews; edited journals/journal sections; given academic lectures in grand rounds, CME events and other clinical/scientific venues; The University of Gibraltar receives funding from the Gibraltar Gambling Care Foundation, an independent, not-for-profit charity generated books or chapters for publishers of mental health texts. The University of Gibraltar receives funding from the Gibraltar Gambling Care Foundation, an independent, not-for-profit charity. However, these funding sources are not related to this study, and the funding institution had no role in the study design or the collection, analysis, and interpretation of the data, the writing of the manuscript, or the decision to submit the paper for publication., (© 2024 The Author(s).)

Bromodomain and extraterminal (BET) proteins are extensively studied in multiple pathologies, including cancer. BET proteins modulate transcription of various genes, including those synonymous with cancer, such as MYC. Thus, BET inhibitors are a major area of drug development efforts. (+)-JQ1 (JQ1) is the prototype inhibitor and is a common tool to probe BET functions. While showing therapeutic promise, JQ1 is not clinically usable, partly due to metabolic instability. Here, we show that JQ1 and the BET-inactive (-)-JQ1 are agonists of pregnane X receptor (PXR), a nuclear receptor that transcriptionally regulates genes encoding drug-metabolizing enzymes such as CYP3A4, which was previously shown to oxidize JQ1. A PXR-JQ1 co-crystal structure identified JQ1's tert-butyl moiety as a PXR anchor and explains binding by (-)-JQ1. Analogs differing at the tert-butyl lost PXR binding, validating our structural findings. Evaluation in liver cell models revealed both PXR-dependent and PXR-independent modulation of CYP3A4 expression by BET inhibitors. We have characterized a non-BET JQ1 target, a mechanism of physiological JQ1 instability, a biological function of (-)-JQ1, and BET-dependent transcriptional regulation of drug metabolism genes., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Epilepsy is a heterogeneous disorder of recurrent seizures which often is comorbid with anxiety, depression, attention deficit hyperactivity disorder (ADHD), intellectual disability (ID), and other psychiatric manifestations. Treating both epilepsy and behavioral symptoms from psychiatric disorders can result in polypharmacy with interactions of medications leading to both worsened efficacy of antiseizure medications due to psychotropic effects and worsening of psychiatric symptoms due to antiseizure medication side effects. We aim to suggest pragmatic strategies for the neurologist in the diagnosis and management of comorbid ADHD in patients with epilepsy based on the International League Against Epilepsy (ILAE) Pediatric Commission guidelines and additional literature review. The screening tool of choice for the symptoms of ADHD is validated in the country of practice and written in the language of the family, though various screening tools and advantages and disadvantages of each will be discussed. Once ADHD is diagnosed, recent safety data suggest that Methylphenidate, Amphetamine, and Atomoxetine are generally safe for patients with epilepsy. We present a case of a child with epilepsy and ADHD and discuss the clinical signs, symptoms, and strategies for treatment as well as when to refer to child psychiatry., Competing Interests: 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., (© 2024 The Author(s).)

Molecular-glue degraders are small molecules that induce a specific interaction between an E3 ligase and a target protein, resulting in the target proteolysis. The discovery of molecular glue degraders currently relies mostly on screening approaches. Here, we describe screening of a library of cereblon (CRBN) ligands against a panel of patient-derived cancer cell lines, leading to the discovery of SJ7095, a potent degrader of CK1α, IKZF1 and IKZF3 proteins. Through a structure-informed exploration of structure activity relationship (SAR) around this small molecule we develop SJ3149, a selective and potent degrader of CK1α protein in vitro and in vivo. The structure of SJ3149 co-crystalized in complex with CK1α + CRBN + DDB1 provides a rationale for the improved degradation properties of this compound. In a panel of 115 cancer cell lines SJ3149 displays a broad antiproliferative activity profile, which shows statistically significant correlation with MDM2 inhibitor Nutlin-3a. These findings suggest potential utility of selective CK1α degraders for treatment of hematological cancers and solid tumors., (© 2024. The Author(s).)

The human nuclear receptor (NR) family of transcription factors contains 48 proteins that bind lipophilic molecules. Approved NR therapies have had immense success treating various diseases, but lack of selectivity has hindered efforts to therapeutically target the majority of NRs due to unpredictable off-target effects. The synthetic ligand T0901317 was originally discovered as a potent agonist of liver X receptors (LXRα/β) but subsequently found to target additional NRs, with activation of pregnane X receptor (PXR) being as potent as that of LXRs. We previously showed that directed rigidity reduces PXR binding by T0901317 derivatives through unfavorable protein remodeling. Here, we use a similar approach to achieve selectivity for PXR over other T0901317-targeted NRs. One molecule, SJPYT-318, accomplishes selectivity by favorably utilizing PXR's flexible binding pocket and surprisingly binding in a new mode distinct from the parental T0901317. Our work provides a structure-guided framework to achieve NR selectivity from promiscuous compounds., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Arrays of coupled nanoelectromechanical resonators are a promising foundation for implementing large-scale network applications, such as mechanical-based information processing and computing, but their practical realization remains an outstanding challenge. In this work, we demonstrate a scalable platform of suspended graphene resonators, such that neighboring resonators are persistently coupled mechanically. We provide evidence of strong coupling between neighboring resonators using two different tuning methods. Additionally, we provide evidence of inter-resonator coupling of higher-order modes, demonstrating the rich dynamics that can be accessed with this platform. Our results establish this platform as a viable option for realizing large-scale programmable networks, enabling applications such as phononic circuits, tunable waveguides, and reconfigurable metamaterials.

Introduction: Despite being a widely used screening questionnaire, there is no consensus on the most appropriate measurement model for the Alcohol Use Disorders Identification Test (AUDIT). Furthermore, there have been limited studies on its measurement invariance across cross-cultural subgroups, genders, and sexual orientations., Aims: The present study aimed to examine the fit of different measurement models for the AUDIT and its measurement invariance across a wide range of subgroups by country, language, gender, and sexual orientation., Methods: Responses concerning past-year alcohol use from the participants of the cross-sectional International Sex Survey were considered (N = 62,943; M age : 32.73; SD = 12.59). Confirmatory factor analysis, as well as measurement invariance tests were performed for 21 countries, 14 languages, three genders, and four sexual-orientation subgroups that met the minimum sample size requirement for inclusion in these analyses., Results: A two-factor model with factors describing 'alcohol use' (items 1-3) and 'alcohol problems' (items 4-10) showed the best model fit across countries, languages, genders, and sexual orientations. For the former two, scalar and latent mean levels of invariance were reached considering different criteria. For gender and sexual orientation, a latent mean level of invariance was reached., Conclusions: In line with the two-factor model, the calculation of separate alcohol-use and alcohol-problem scores is recommended when using the AUDIT. The high levels of measurement invariance achieved for the AUDIT support its use in cross-cultural research, capable also of meaningful comparisons among genders and sexual orientations., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest with the content of this manuscript. SWK discloses that he has received funding from the International Center for Responsible Gaming, MGM Resorts International, Center for the Application of Substance Abuse Technologies, Taylor Francis, Springer Nature, The Nevada Problem Gambling Project, Sports Betting Alliance, and Kindbridge Research Institute. Dr. Potenza discloses that he has consulted for and advised Game Day Data, Addiction Policy Forum, AXA, Idorsia, Baria-Tek, and Opiant Therapeutics; been involved in a patent application involving Novartis and Yale; received research support from the Mohegan Sun Casino and the Connecticut Council on Problem Gambling; consulted for or advised legal and gambling entities on issues related to impulse control and addictive behaviors; provided clinical care related to impulse-control and addictive behaviors; performed grant reviews; edited journals/journal sections; given academic lectures in grand rounds, CME events and other clinical/scientific venues; and generated books or chapters for publishers of mental health texts. The University of Gibraltar receives funding from the Gibraltar Gambling Care Foundation, an independent, notfor-profit charity. ELTE Eötvös Loránd University receives funding from Szerencsejáték Ltd. (the gambling operator of the Hungarian government) to maintain a telephone helpline service for problematic gambling. RG is the shareholder of Adiquit Ltd. which is currently developing apps for addictions recovery. VS discloses that she received funding from Lithuanian Health Promotion Fund for providing educational materials and lectures on Problematic Internet use. Julius Burkauskas works as consultant at Cronos., (Copyright © 2023. Published by Elsevier Inc.)

Deep-sea lineages are generally thought to arise from shallow-water ancestors, but this hypothesis is based on a relatively small number of taxonomic groups. Anthozoans, which include corals and sea anemones, are significant contributors to the faunal diversity of the deep sea, but the timing and mechanisms of their invasion into this biome remain elusive. Here, we reconstruct a fully resolved, time-calibrated phylogeny of 83 species in the order Antipatharia (black coral) to investigate their bathymetric evolutionary history. Our reconstruction indicates that extant black coral lineages first diversified in continental slope depths (∼250-3000 m) during the early Silurian (∼437 millions of years ago (Ma)) and subsequently radiated into, and diversified within, both continental shelf (less than 250 m) and abyssal (greater than 3000 m) habitats. Ancestral state reconstruction analysis suggests that the appearance of morphological features that enhanced the ability of black corals to acquire nutrients coincided with their invasion of novel depths. Our findings have important conservation implications for anthozoan lineages, as the loss of 'source' slope lineages could threaten millions of years of evolutionary history and confound future invasion events, thereby warranting protection.

Sperm storage by females after mating for species-dependent periods is used widely among animals with internal fertilization to allow asynchrony between mating and ovulation. Many mammals store sperm in the lower oviduct where specific glycans on oviduct epithelial cells retain sperm to form a reservoir. Binding to oviduct cells suppresses sperm intracellular Ca2+ and increases sperm longevity. We investigated the mechanisms by which a specific oviduct glycan, 3-O-sulfated Lewis X trisaccharide (suLeX), prolongs the lifespan of porcine sperm. Using targeted metabolomics, we found that binding to suLeX diminishes the abundance of 4-hydroxybenzoic acid, the precursor to ubiquinone (also known as Coenzyme Q), 30 min after addition. Ubiquinone functions as an electron acceptor in the electron transport chain (ETC). 3-O-sulfated Lewis X trisaccharide also suppressed the formation of fumarate. A component of the citric acid cycle, fumarate is synthesized by succinate-coenzyme Q reductase, which employs ubiquinone and is also known as Complex II in the ETC. Consistent with the reduced activity of the ETC, the production of harmful reactive oxygen species (ROS) was diminished. The enhanced sperm lifespan in the oviduct may be because of suppressed ROS production because high ROS concentrations have toxic effects on sperm., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Recent sleep guidelines regarding evening exercise have shifted from a conservative (i.e., do not exercise in the evening) to a more nuanced approach (i.e., exercise may not be detrimental to sleep in circumstances). With the increasing popularity of wearable technology, information regarding exercise and sleep are readily available to the general public. There is potential for these data to aid sleep recommendations within and across different population cohorts. Therefore, the aim of this study was to examine if sleep, exercise, and individual characteristics can be used to predict whether evening exercise will compromise sleep. Methods: Data regarding evening exercise and the subsequent night's sleep were obtained from 5,250 participants (1,321F, 3,929M, aged 30.1 ± 5.2 yrs) using a wearable device (WHOOP 3.0). Data for females and males were analysed separately. The female and male datasets were both randomly split into subsets of training and testing data (training:testing = 75:25). Algorithms were trained to identify compromised sleep (i.e., sleep efficiency <90%) for females and males based on factors including the intensity, duration and timing of evening exercise. Results: When subsequently evaluated using the independent testing datasets, the algorithms had sensitivity for compromised sleep of 87% for females and 90% for males, specificity of 29% for females and 20% for males, positive predictive value of 32% for females and 36% for males, and negative predictive value of 85% for females and 79% for males. If these results generalise, applying the current algorithms would allow females to exercise on ~ 25% of evenings with ~ 15% of those sleeps being compromised and allow males to exercise on ~ 17% of evenings with ~ 21% of those sleeps being compromised. Discussion: The main finding of this study was that the models were able to predict a high percentage of nights with compromised sleep based on individual characteristics, exercise characteristics and habitual sleep characteristics. If the benefits of exercising in the evening outweigh the costs of compromising sleep on some of the nights when exercise is undertaken, then the application of the current algorithms could be considered a viable alternative to generalised sleep hygiene guidelines., Competing Interests: EC is a stakeholder and employee of WHOOP Inc. DM, GR, and CS are part of a research group in which WHOOP Inc. provides research funding. The remaining author declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Miller, Roach, Lastella, Capodilupo and Sargent.)

Spinal cord infarctions in children are rare and early magnetic resonance imaging studies are often negative. A high clinical suspicion must be maintained to identify stroke and initiate workup for underlying etiology to suggest appropriate treatment. We present two cases of spinal cord infarction without major preceding trauma. The first was caused by disc herniation and external impingement of a radiculomedullary artery and the second was due to fibrocartilaginous embolism with classic imaging findings of ventral and dorsal cord infarctions, respectively. These cases were treated conservatively with diagnostic workup and aspirin, though additional treatments which can be considered with prompt diagnosis are also explored in our discussion. Both cases recovered the ability to ambulate independently within months. Case 1 is attending college and ambulates campus with a single-point cane. Case 2 ambulates independently, though has some difficulty with proprioception of the feet so uses wheelchairs for long-distance ambulation., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Brain Circulation.)

Background and Aims: Despite its inclusion in the 11th revision of the International Classification of Diseases, there is a virtual paucity of high-quality scientific evidence about compulsive sexual behavior disorder (CSBD), especially in underrepresented and underserved populations. Therefore, we comprehensively examined CSBD across 42 countries, genders, and sexual orientations, and validated the original (CSBD-19) and short (CSBD-7) versions of the Compulsive Sexual Behavior Disorder Scale to provide standardized, state-of-the-art screening tools for research and clinical practice., Method: Using data from the International Sex Survey (N = 82,243; Mage = 32.39 years, SD = 12.52), we evaluated the psychometric properties of the CSBD-19 and CSBD-7 and compared CSBD across 42 countries, three genders, eight sexual orientations, and individuals with low vs. high risk of experiencing CSBD., Results: A total of 4.8% of the participants were at high risk of experiencing CSBD. Country- and gender-based differences were observed, while no sexual-orientation-based differences were present in CSBD levels. Only 14% of individuals with CSBD have ever sought treatment for this disorder, with an additional 33% not having sought treatment because of various reasons. Both versions of the scale demonstrated excellent validity and reliability., Discussion and Conclusions: This study contributes to a better understanding of CSBD in underrepresented and underserved populations and facilitates its identification in diverse populations by providing freely accessible ICD-11-based screening tools in 26 languages. The findings may also serve as a crucial building block to stimulate research into evidence-based, culturally sensitive prevention and intervention strategies for CSBD that are currently missing from the literature.

This report describes a 3D microelectrode array integrated on a thin-film flexible cable for neural recording in small animals. The fabrication process combines traditional silicon thin-film processing techniques and direct laser writing of 3D structures at micron resolution via two-photon lithography. Direct laser-writing of 3D-printed electrodes has been described before, but this report is the first to provide a method for producing high-aspect-ratio structures. One prototype, a 16-channel array with 300 µm pitch, demonstrates successful electrophysiological signal capture from bird and mouse brains. Additional devices include 90 µm pitch arrays, biomimetic mosquito needles that penetrate through the dura of birds, and porous electrodes with enhanced surface area. The rapid 3D printing and wafer-scale methods described here will enable efficient device fabrication and new studies examining the relationship between electrode geometry and electrode performance. Applications include small animal models, nerve interfaces, retinal implants, and other devices requiring compact, high-density 3D electrodes., (© 2023. The Author(s).)

The contribution of sperm to embryogenesis is gaining attention with up to 50% of infertility cases being attributed to a paternal factor. The traditional methods used in assisted reproductive technologies for selecting and assessing sperm quality are mainly based on motility and viability parameters. However, other sperm characteristics, including deoxyribonucleic acid integrity, have major consequences for successful live birth. In natural reproduction, sperm navigate the male and female reproductive tract to reach and fertilize the egg. During transport, sperm encounter many obstacles that dramatically reduce the number arriving at the fertilization site. In humans, the number of sperm is reduced from tens of millions in the ejaculate to hundreds in the Fallopian tube (oviduct). Whether this sperm population has higher fertilization potential is not fully understood, but several studies in animals indicate that many defective sperm do not advance to the site of fertilization. Moreover, the oviduct plays a key role in fertility by modulating sperm transport, viability, and maturation, providing sperm that are ready to fertilize at the appropriate time. Here we present evidence of sperm selection by the oviduct with emphasis on the mechanisms of selection and the sperm characteristics selected. Considering the sperm parameters that are essential for healthy embryonic development, we discuss the use of novel in vitro sperm selection methods that mimic physiological conditions. We propose that insight gained from understanding how the oviduct selects sperm can be translated to assisted reproductive technologies to yield high fertilization, embryonic development, and pregnancy rates., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Seafloor methane emissions can affect Earth's climate and ocean chemistry. Vast quantities of methane formed by microbial decomposition of organic matter are locked within gas hydrate and free gas on continental slopes, particularly in large areas with high sediment accumulations such as deep-sea fans. The release of methane in slope environments has frequently been associated with dissociation of gas hydrates near the edge of the gas hydrate stability zone on the upper slope, with discharges in greater water depths less understood. Here we show, using data from the Rio Grande Cone (western South Atlantic), that the intrinsic, gravity-induced downslope collapse of thick slope sediment accumulations creates structures that serve as pathways for gas migration, unlocking methane and causing seafloor emissions via giant gas flares in the water column. The observed emissions in the study region (up to 310 Mg year -1 ) are three times greater than estimates for the entire US North Atlantic margin and reveal the importance of collapsing sediment accumulations for ocean carbon cycling. Similar outgassing systems on the Amazon and Niger fans suggest that gravity tectonics on passive margins is a common yet overlooked mechanism driving massive seafloor methane emissions in sediment-laden continental slopes., (© 2023. The Author(s).)

Ligand-binding promiscuity in detoxification systems protects the body from toxicological harm but is a roadblock to drug development due to the difficulty in optimizing small molecules to both retain target potency and avoid metabolic events. Immense effort is invested in evaluating metabolism of molecules to develop safer, more effective treatments, but engineering specificity into or out of promiscuous proteins and their ligands is a challenging task. To better understand the promiscuous nature of detoxification networks, we have used X-ray crystallography to characterize a structural feature of pregnane X receptor (PXR), a nuclear receptor that is activated by diverse molecules (with different structures and sizes) to up-regulate transcription of drug metabolism genes. We found that large ligands expand PXR's ligand-binding pocket, and the ligand-induced expansion occurs through a specific unfavorable compound-protein clash that likely contributes to reduced binding affinity. Removing the clash by compound modification resulted in more favorable binding modes with significantly enhanced binding affinity. We then engineered the unfavorable ligand-protein clash into a potent, small PXR ligand, resulting in marked reduction in PXR binding and activation. Structural analysis showed that PXR is remodeled, and the modified ligands reposition in the binding pocket to avoid clashes, but the conformational changes result in less favorable binding modes. Thus, ligand-induced binding pocket expansion increases ligand-binding potential of PXR but is an unfavorable event; therefore, drug candidates can be engineered to expand PXR's ligand-binding pocket and reduce their safety liability due to PXR binding.

Opsins, light-sensitive G protein-coupled receptors, have been identified in corals but their properties are largely unknown. Here, we identified six opsin genes (acropsins 1-6) from a coral species Acropora millepora, including three novel opsins (acropsins 4-6), and successfully characterized the properties of four out of the six acropsins. Acropsins 1 and 6 exhibited light-dependent cAMP increases in cultured cells, suggesting that the acropsins could light-dependently activate Gs-type G protein like the box jellyfish opsin from the same opsin group. Spectral sensitivity curves having the maximum sensitivities at ~ 472 nm and ~ 476 nm were estimated for acropsins 1 and 6, respectively, based on the light wavelength-dependent cAMP increases in these opsins-expressing cells (heterologous action spectroscopy). Acropsin 2 belonging to the same group as acropsins 1 and 6 did not induce light-dependent cAMP or Ca 2+ changes. We then successfully estimated the acropsin 2 spectral sensitivity curve having its maximum value at ~ 471 nm with its chimera mutant which possessed the third cytoplasmic loop of the Gs-coupled jellyfish opsin. Acropsin 4 categorized as another group light-dependently induced intracellular Ca 2+ increases but not cAMP changes. Our results uncovered that the Acropora coral possesses multiple opsins coupling two distinct cascades, cyclic nucleotide and Ca 2+ signaling light-dependently., (© 2023. The Author(s).)

Sperm storage by females after mating for species-dependent periods is used widely among animals with internal fertilization to allow asynchrony between mating and ovulation. Many mammals store sperm in the lower oviduct where specific glycans on epithelial cells retain sperm to form a reservoir. Binding to oviduct cells suppresses sperm intracellular Ca 2+ and increases sperm longevity. We investigated the mechanisms by which a specific oviduct glycan, 3-O-sulfated Lewis X trisaccharide (suLe X ), prolongs the lifespan of porcine sperm. Using targeted metabolomics, we report that binding to suLe X diminishes the abundance of the precursor to ubiquinone and suppresses formation of fumarate, a specific citric acid cycle component, diminishing the activity of the electron transport chain and reducing the production of harmful reactive oxygen species (ROS). The enhanced sperm lifespan in the oviduct may be due to suppressed ROS production as many reports have demonstrated toxic effects of high ROS concentrations on sperm.

Background and Purpose: Mechanical thrombectomy (MT) is the standard treatment for large vessel occlusion (LVO) acute ischemic stroke. Patients with active malignancy have an increased risk of stroke but were excluded from MT trials., Methods: We searched the National Readmission Database for LVO patients treated with MT between 2016-2018 and compared the characteristics and outcomes of cancer-free patients to those with metastatic cancer (MC). Primary outcomes were all-cause in-hospital mortality and favorable outcome, defined as a routine discharge to home (regardless of whether home services were provided or not). Multivariate regression was used to adjust for confounders., Results: Of 40,537 LVO patients treated with MT, 933 (2.3%) had MC diagnosis. Compared to cancer-free patients, MC patients were similar in age and stroke severity but had greater overall disease severity. Hospital complications that occurred more frequently in MC included pneumonia, sepsis, acute coronary syndrome, deep vein thrombosis, and pulmonary embolism (P<0.001). Patients with MC had similar rates of intracerebral hemorrhage (20% vs. 21%) but were less likely to receive tissue plasminogen activator (13% vs. 23%, P<0.001). In unadjusted analysis, MC patients as compared to cancer-free patients had a higher in-hospital mortality rate and were less likely to be discharged to home (36% vs. 42%, P=0.014). On multivariate regression adjusting for confounders, mortality was the only outcome that was significantly higher in the MC group than in the cancerfree group (P<0.001)., Conclusion: LVO patients with MC have higher mortality and more infectious and thrombotic complications than cancer-free patients. MT nonetheless can result in survival with good outcome in slightly over one-third of patients.

Climate change threatens the survival of coral reefs on a global scale, primarily through mass bleaching and mortality as a result of marine heatwaves. While these short-term effects are clear, predicting the fate of coral reefs over the coming century is a major challenge. One way to understand the longer-term effects of rapid climate change is to examine the response of coral populations to past climate shifts. Coastal and shallow-water marine ecosystems such as coral reefs have been reshaped many times by sea-level changes during the Pleistocene, yet, few studies have directly linked this with its consequences on population demographics, dispersal, and adaptation. Here we use powerful analytical techniques, afforded by haplotype phased whole-genomes, to establish such links for the reef-building coral, Acropora digitifera. We show that three genetically distinct populations are present in northwestern Australia, and that their rapid divergence since the last glacial maximum (LGM) can be explained by a combination of founder-effects and restricted gene flow. Signatures of selective sweeps, too strong to be explained by demographic history, are present in all three populations and overlap with genes that show different patterns of functional enrichment between inshore and offshore habitats. In contrast to rapid divergence in the host, we find that photosymbiont communities are largely undifferentiated between corals from all three locations, spanning almost 1000 km, indicating that selection on host genes and not acquisition of novel symbionts, has been the primary driver of adaptation for this species in northwestern Australia., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Environmental epidemiology has proven critical to study various associations between environmental exposures and adverse human health effects. However, there is a perception that it often does not sufficiently inform quantitative risk assessment. To help address this concern, in 2017, the Health and Environmental Sciences Institute initiated a project engaging the epidemiology, exposure science, and risk assessment communities with tripartite representation from government agencies, industry, and academia, in a dialogue on the use of environmental epidemiology for quantitative risk assessment and public health decision making. As part of this project, four meetings attended by experts in epidemiology, exposure science, toxicology, statistics, and risk assessment, as well as one additional meeting engaging funding agencies, were organized to explore incentives and barriers to realizing the full potential of epidemiological data in quantitative risk assessment. A set of questions was shared with workshop participants prior to the meetings, and two case studies were used to support the discussion. Five key ideas emerged from these meetings as areas of desired improvement to ensure that human data can more consistently become an integral part of quantitative risk assessment: 1) reducing confirmation and publication bias, 2) increasing communication with funding agencies to raise awareness of research needs, 3) developing alternative funding channels targeted to support quantitative risk assessment, 4) making data available for reuse and analysis, and 5) developing cross-disciplinary and cross-sectoral interactions, collaborations, and training. We explored and integrated these themes into a roadmap illustrating the need for a multi-stakeholder effort to ensure that epidemiological data can fully contribute to the quantitative evaluation of human health risks, and to build confidence in a reliable decision-making process that leverages the totality of scientific evidence., (© 2022 The Authors.)

The primary aim of this study was to examine the validity of six commonly used wearable devices, i.e., Apple Watch S6, Garmin Forerunner 245 Music, Polar Vantage V, Oura Ring Generation 2, WHOOP 3.0 and Somfit, for assessing sleep. The secondary aim was to examine the validity of the six devices for assessing heart rate and heart rate variability during, or just prior to, night-time sleep. Fifty-three adults (26 F, 27 M, aged 25.4 ± 5.9 years) spent a single night in a sleep laboratory with 9 h in bed (23:00-08:00 h). Participants were fitted with all six wearable devices-and with polysomnography and electrocardiography for gold-standard assessment of sleep and heart rate, respectively. Compared with polysomnography, agreement (and Cohen's kappa) for two-state categorisation of sleep periods (as sleep or wake) was 88% (κ = 0.30) for Apple Watch; 89% (κ = 0.35) for Garmin; 87% (κ = 0.44) for Polar; 89% (κ = 0.51) for Oura; 86% (κ = 0.44) for WHOOP and 87% (κ = 0.48) for Somfit. Compared with polysomnography, agreement (and Cohen's kappa) for multi-state categorisation of sleep periods (as a specific sleep stage or wake) was 53% (κ = 0.20) for Apple Watch; 50% (κ = 0.25) for Garmin; 51% (κ = 0.28) for Polar; 61% (κ = 0.43) for Oura; 60% (κ = 0.44) for WHOOP and 65% (κ = 0.52) for Somfit. Analyses regarding the two-state categorisation of sleep indicate that all six devices are valid for the field-based assessment of the timing and duration of sleep. However, analyses regarding the multi-state categorisation of sleep indicate that all six devices require improvement for the assessment of specific sleep stages. As the use of wearable devices that are valid for the assessment of sleep increases in the general community, so too does the potential to answer research questions that were previously impractical or impossible to address-in some way, we could consider that the whole world is becoming a sleep laboratory.

Sulfonolipids are unusual lipids found in the outer membranes of Gram-negative bacteria in the phylum Bacteroidetes. Sulfonolipid and its deacylated derivative, capnine, are sulfur analogs of ceramide-1-phosphate and sphingosine-1-phosphate, respectively; thus, sulfonolipid biosynthesis is postulated to be similar to the sphingolipid biosynthetic pathway. Here, we identify the first enzyme in sulfonolipid synthesis in Alistipes finegoldii as the product of the alfi&#95;1224 gene, cysteate acyl-acyl carrier protein (ACP) transferase (SulA). We show SulA catalyzes the condensation of acyl-ACP and cysteate (3-sulfo-alanine) to form 3-ketocapnine. Acyl-CoA is a poor substrate. We show SulA has a bound pyridoxal phosphate (PLP) cofactor that undergoes a spectral redshift in the presence of cysteate, consistent with the transition of the lysine-aldimine complex to a substrate-aldimine complex. Furthermore, the SulA crystal structure shows the same prototypical fold found in bacterial serine palmitoyltransferases (Spts), enveloping the PLP cofactor bound to Lys251. We observed the SulA and Spt active sites are identical except for Lys281 in SulA, which is an alanine in Spt. Additionally, SulA(K281A) is catalytically inactive but binds cysteate and forms the external aldimine normally, highlighting the structural role of the Lys281 side chain in walling off the active site from bulk solvent. Finally, the electropositive groove on the protein surface adjacent to the active site entrance provides a landing pad for the electronegative acyl-ACP surface. Taken together, these data identify the substrates, products, and mechanism of SulA, the PLP-dependent condensing enzyme that catalyzes the first step in sulfonolipid synthesis in a gut commensal bacterium., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to examine sleep/wake behaviour and sleep strategies before, during and after ultra-marathon running events exceeding 100 miles (161 km). A total of 119 athletes completed a web-based questionnaire regarding their habitual sleep/wake behaviour before, during, and after ultra-marathon participation. Event-specific data were grouped by race distance categories; 100-149 miles (161-240 km), 150-199 miles (241-321 km), and ≥200 miles (322 km). Athletes commonly reported not sleeping throughout the duration of their races (74%). However, for events that were ≥200 miles, athletes reported more sleep opportunities, longer sleep duration, and more total sleep when compared to events that were 100-149 miles in distance ( p ≤ 0.001). This suggests that for races of shorter distances, the benefit of continuous racing outweighs the negative impact of continuous wakefulness/sleep deprivation. However, for longer races (≥200 miles), there is an apparent tradeoff between sleep deprivation and race strategy, whereby athletes cannot sustain a desired level of performance without obtaining sleep. This is consistent with established sleep/wake behaviour models suggesting that sleep need increases as wakefulness increases, or in this case, as race duration increases. For athletes participating in ultra-marathons, sleep management education and/or consultation with a sleep scientist prior to racing may be beneficial. Future research should examine the optimal strategies concerning the frequency and duration of sleep during ultra-marathons and the subsequent impact on performance.

In mammalian females, after sperm are deposited in the reproductive tract, a fraction of sperm migrates to the lower oviduct (isthmus) and forms a sperm storage site known as the functional sperm reservoir. The interactions between sperm membrane proteins and oviduct epithelial cells facilitate sperm binding to the oviductal epithelium and retention in the reservoir. Sperm are bound by glycans that contain specific motifs present on isthmic epithelial cells. Capacitated sperm are released from the reservoir and travel further in the oviduct to the ampulla where fertilization occurs. For decades, researchers have been studying the molecules and mechanisms of sperm release from the oviductal sperm reservoir. However, it is still not clear if the release of sperm is triggered by changes in sperm, oviduct cells, oviduct fluid, or a combination of these. While there is a possibility that more than one of these events are involved in the release of sperm from the reservoir, one activator of sperm release has the largest accumulation of supporting evidence. This mechanism involves the steroid hormone, progesterone, as a signal that induces the release of sperm from the reservoir. This review gathers and synthesizes evidence for the role of progesterone in inducing sperm release from the oviduct functional sperm reservoir.

Fertilizing sperm are retained by adhesion to specific glycans on the epithelium of the oviduct forming a reservoir before sperm are released from the reservoir so fertilization can ensue. Capacitated sperm lose affinity for the oviduct epithelium but the components of capacitation that are important for sperm release are uncertain. One important correlate of capacitation is the development of hyperactivated motility. Hyperactivation is characterized by asymmetrical flagellar beating with high beat amplitude. We tested whether the development of full-type asymmetrical motility was sufficient to release sperm from immobilized oviduct glycans. Sperm hyperactivation was induced by four different compounds, a cell-permeable cAMP analog (cBiMPS), CatSper activators (4-aminopyridine and procaine), and an endogenous steroid (progesterone). Using standard analysis (CASA) and direct visualization with high-speed video microscopy, we first confirmed that all four compounds induced hyperactivation. Subsequently, sperm were allowed to bind to immobilized oviduct glycans, and compounds or vehicle controls were added. All compounds caused sperm release from immobilized glycans, demonstrating that hyperactivation was sufficient to release sperm from oviduct cells and immobilized glycans. Pharmacological inhibition of the non-genomic progesterone receptor and CatSper diminished sperm release from oviduct glycans. Inhibition of the proteolytic activities of the ubiquitin-proteasome system (UPS), implicated in the regulation of sperm capacitation, diminished sperm release in response to all hyperactivation inducers. In summary, induction of sperm hyperactivation was sufficient to induce sperm release from immobilized oviduct glycans and release was dependent on CatSper and the UPS., (© 2022. The Author(s).)

The aim of this study was to examine the sleep-wake behaviour of 200-mile ultra-marathon runners before, during, and after a competition. A longitudinal, observational study was conducted to collect the sleep data of four (two females; mean age: 45.5 ± 3.1 years) runners competing in a 200-mile ultra-marathon (N = 4). Wrist-worn activity monitors, in conjunction with self-report sleep diaries, were used to measure sleep, beginning seven days prior to the race and concluding seven days following the race (2-19 June 2021). Descriptive analysis of runners' subjective and objective sleep data was conducted. All runners completed the 200-mile event in an average of 82.5 ± 7.1 h. On average, runners obtained 4.7 ± 3.0 h of sleep from 4.8 ± 2.4 sleep episodes, averaging 59.9 ± 49.2 min of sleep per episode. Runners averaged 6.0 ± 1.3 h of sleep per night in the week before the competition and 6.3 ± 1.3 h per night in the week following the competition. Runners in the 200-mile (326 km) ultra-marathon drastically restricted their sleep. However, obtained sleep, the number of sleep episodes, and sleep episode length were greater than those previously reported with 100-mile (161 km) runners. In-race sleep data suggest an increased need for sleep as race duration increases. Interestingly, runners obtained less than the recommended ~8 h of sleep per night, in both pre-race and post-race phases of the competition.

With wide deployment of deep neural network (DNN) classifiers, there is great potential for harm from adversarial learning attacks. Recently, a special type of data poisoning (DP) attack, known as a backdoor (or Trojan), was proposed. These attacks do not seek to degrade classification accuracy, but rather to have the classifier learn to classify to a target class t ∗ whenever the backdoor pattern is present in a test example originally from a source class s ∗ . Launching backdoor attacks does not require knowledge of the classifier or its training process-only the ability to poison the training set with exemplars containing a backdoor pattern (labeled with the target class). Defenses against backdoors can be deployed before/during training, post-training, or at test time. Here, we address post-training detection in DNN image classifiers, seldom considered in existing works, wherein the defender does not have access to the poisoned training set, but only to the trained classifier itself, as well as to clean (unpoisoned) examples from the classification domain. This scenario is of great interest because e.g., a classifier may be the basis of a phone app that will be shared with many users. Detection may thus reveal a widespread attack. We propose a purely unsupervised anomaly detection (AD) defense against imperceptible backdoor attacks that: 1) detects whether the trained DNN has been backdoor-attacked; 2) infers the source and target classes in a detected attack; 3) estimates the backdoor pattern itself. Our AD approach involves learning (via suitable cost function minimization) the minimum size/norm perturbation (putative backdoor) required to induce the classifier to misclassify (most) examples from class s to class t , for all (s,t) pairs. Our hypothesis is that nonattacked pairs require large perturbations, while the attacked pair (s ∗ , t ∗ ) requires much smaller ones. This is convincingly borne out experimentally. We identify a variety of plausible cost functions and devise a novel, robust hypothesis testing approach to perform detection inference. We test our approach, in comparison with the state-of-the-art methods, for several backdoor patterns, attack settings and mechanisms, and data sets and demonstrate its favorability. Our defense essentially requires setting a single hyperparameter (the detection threshold), which can e.g., be chosen to fix the system's false positive rate.

Considerable attention has recently been focused on the potential involvement of DNA methylation in regulating gene expression in cnidarians. Much of this work has been centered on corals, in the context of changes in methylation perhaps facilitating adaptation to higher seawater temperatures and other stressful conditions. Although first proposed more than 30 years ago, the possibility that DNA methylation systems function in protecting animal genomes against the harmful effects of transposon activity has largely been ignored since that time. Here, we show that transposons are specifically targeted by the DNA methylation system in cnidarians, and that the youngest transposons (i.e., those most likely to be active) are most highly methylated. Transposons in longer and highly active genes were preferentially methylated and, as transposons aged, methylation levels declined, reducing the potentially harmful side effects of CpG methylation. In Cnidaria and a range of other invertebrates, correlation between the overall extent of methylation and transposon content was strongly supported. Present transposon burden is the dominant factor in determining overall level of genomic methylation in a range of animals that diverged in or before the early Cambrian, suggesting that genome defense represents the ancestral role of CpG methylation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Basilar artery dolichoectasia can lead to ischemic stroke through thrombosis of small perforating vessels of the brainstem. Here we report the case of a patient with transient paramedian pontine syndrome in the setting of a hypertensive crisis, finding a dolichoectasia basilar artery compressing on the ventral surface of the pons. The outcome was near-complete resolution of deficits after blood pressure control. We propose increased basilar artery pulse pressure as a novel mechanism of transient compression of the brainstem by a dolichoectasia artery.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that regulates important functions in the central nervous system 1,2 . The ALK gene is a hotspot for chromosomal translocation events that result in several fusion proteins that cause a variety of human malignancies 3 . Somatic and germline gain-of-function mutations in ALK were identified in paediatric neuroblastoma 4-7 . ALK is composed of an extracellular region (ECR), a single transmembrane helix and an intracellular tyrosine kinase domain 8,9 . ALK is activated by the binding of ALKAL1 and ALKAL2 ligands 10-14 to its ECR, but the lack of structural information for the ALK-ECR or for ALKAL ligands has limited our understanding of ALK activation. Here we used cryo-electron microscopy, nuclear magnetic resonance and X-ray crystallography to determine the atomic details of human ALK dimerization and activation by ALKAL1 and ALKAL2. Our data reveal a mechanism of RTK activation that allows dimerization by either dimeric (ALKAL2) or monomeric (ALKAL1) ligands. This mechanism is underpinned by an unusual architecture of the receptor-ligand complex. The ALK-ECR undergoes a pronounced ligand-induced rearrangement and adopts an orientation parallel to the membrane surface. This orientation is further stabilized by an interaction between the ligand and the membrane. Our findings highlight the diversity in RTK oligomerization and activation mechanisms., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The primary aims of the present study were to examine the impact of chronotype on sleep/wake behaviour, perceived exertion, and training load among professional footballers. Thirty-six elite female professional football player's (mean ± SD: age, 25 ± 4 y; weight, 68 ± 7 kg) sleep and training behaviours were examined for 10 consecutive nights during a pre-season period using a self-report online player-management system and wrist activity monitors. All athletes completed the Morningness-Eveningness Questionnaire (rMEQ) on the first day of data collection. Eleven participants were morning types, seventeen participants were intermediate types, and three participants were evening types. Separate linear mixed models were conducted to assess differences in sleep, perceived exertion, and training behaviours between chronotype groups. Morning types woke up earlier (wake time: 07:19 ± 01:16 vs. 07:53 ± 01:01, p = 0.04) and reported higher ratings of perceived exertion compared to intermediate types (6.7 ± 1.1 vs. 5.9 ± 1.2, p = 0.01). No differences were observed between chronotype groups for bedtime, time in bed, total sleep time, sleep efficiency, training duration, or training load. In circumstances where professional female football players are required to train at a time opposing their natural circadian preference (e.g., morning type training in the evening), their perceived exertion during training may be higher than that of players that are training at a time that aligns with their natural circadian preference (e.g., evening type training in the evening). It is important for practitioners to monitor individual trends in training variables (e.g., rating of perceived exertion, training load) with relation to athlete chronotype and training time. Future research should examine the relationship between chronotype, training time, and rating of perceived exertion across different training durations.

Coral reefs across the globe are threatened by warming oceans. The last few years have seen the worst mass coral bleaching events recorded, with more than one quarter of all reefs irreversibly impacted. Considering the widespread devastation, we need to increase our efforts to understanding the physiological and metabolic shifts underlying the breakdown of this important symbiotic ecosystem. Here, we investigated the proteome (PRIDE accession # PXD011668) of both host and symbionts of the reef-building coral Acropora millepora exposed to ambient (~ 28 °C) and elevated temperature (~ 32 °C for 2 days, following a five-day incremental increase) and explored associated biomolecular changes in the symbiont, with the aim of gaining new insights into the mechanisms underpinning the collapse of the coral symbiosis. We identified 1,230 unique proteins (774 host and 456 symbiont) in the control and thermally stressed corals, of which 107 significantly increased and 125 decreased in abundance under elevated temperature relative to the control. Proteins involved in oxidative stress and proteolysis constituted 29% of the host proteins that increased in abundance, with evidence of impairment to endoplasmic reticulum and cytoskeletal regulation proteins. In the symbiont, we detected a decrease in proteins responsible for photosynthesis and energy production (33% of proteins decreased in abundance), yet minimal signs of oxidative stress or proteolysis. Lipid stores increased > twofold despite reduction in photosynthesis, suggesting reduced translocation of carbon to the host. There were significant changes in proteins related to symbiotic state, including proteins linked to nitrogen metabolism in the host and the V-ATPase (-0.6 fold change) known to control symbiosome acidity. These results highlight key differences in host and symbiont proteomic adjustments under elevated temperature and identify two key proteins directly involved in bilateral nutrient exchange as potential indicators of symbiosis breakdown., (© 2021. The Author(s).)

The COVID-19 pandemic incited unprecedented restrictions on the behavior of society. The aims of this study were to quantify changes to sleep/wake behavior and exercise behavior, as well as changes in physiological markers of health during COVID-19 physical distancing. A retrospective analysis of 5,436 US-based subscribers to the WHOOP platform (mean age = 40.25 ± 11.33; 1,536 females, 3,900 males) was conducted covering the period from January 1st, 2020 through May 15th, 2020. This time period was separated into a 68-day baseline period and a 67-day physical distancing period. To provide context and allow for potential confounders (e.g., change of season), data were also extracted from the corresponding time periods in 2019. As compared to baseline, during physical distancing, all subjects fell asleep earlier (-0.15 hours), woke up later (0.29 hours), obtained more sleep (+0.21 hours) and reduced social jet lag (-0.13 hours). Contrasting sleep behavior was seen in 2019, with subjects falling asleep and waking up at a similar time (-0.01 hours; -0.03 hours), obtaining less sleep (-0.14 hours) and maintaining social jet lag (+0.06 hours) in corresponding periods. Individuals exercised more intensely during physical distancing by increasing the time spent in high heart rate zones. In 2020, resting heart rate decreased (-0.90 beats per minute) and heart rate variability increased (+0.98 milliseconds) during physical distancing when compared to baseline. However, similar changes were seen in 2019 for RHR (-0.51 beats per minute) and HRV (+2.97 milliseconds), suggesting the variation may not be related to the introduction of physical distancing mandates. The findings suggest that individuals improved health related behavior (i.e., increased exercise intensity and longer sleep duration) during physical distancing restrictions. While positive changes were seen to cardiovascular indicators of health, it is unclear whether these changes were a direct consequence of behavior change., Competing Interests: The authors have read the journal’s policy and have the following competing interests: Emily R. Capodilupo is a shareholder and employee of Whoop, Inc. Whoop, Inc is sponsoring the Research Officership of Dean J. Miller. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials

The aims of this study were to: (1) compare actigraphy (ACTICAL) and a commercially available sleep wearable (i.e., WHOOP) under two functionalities (i.e., sleep auto-detection (WHOOP-AUTO) and manual adjustment of sleep (WHOOP-MANUAL)) for two-stage categorisation of sleep (sleep or wake) against polysomnography, and; (2) compare WHOOP-AUTO and WHOOP-MANUAL for four-stage categorisation of sleep (wake, light sleep, slow wave sleep (SWS), or rapid eye movement sleep (REM)) against polysomnography. Six healthy adults (male: n = 3; female: n = 3; age: 23.0 ± 2.2 yr) participated in the nine-night protocol. Fifty-four sleeps assessed by ACTICAL, WHOOP-AUTO and WHOOP-MANUAL were compared to polysomnography using difference testing, Bland-Altman comparisons, and 30-s epoch-by-epoch comparisons. Compared to polysomnography, ACTICAL overestimated total sleep time (37.6 min) and underestimated wake (-37.6 min); WHOOP-AUTO underestimated SWS (-15.5 min); and WHOOP-MANUAL underestimated wake (-16.7 min). For ACTICAL, sensitivity for sleep, specificity for wake and overall agreement were 98%, 60% and 89%, respectively. For WHOOP-AUTO, sensitivity for sleep, wake, and agreement for two-stage and four-stage categorisation of sleep were 90%, 60%, 86% and 63%, respectively. For WHOOP-MANUAL, sensitivity for sleep, wake, and agreement for two-stage and four-stage categorisation of sleep were 97%, 45%, 90% and 62%, respectively. WHOOP-AUTO and WHOOP-MANUAL have a similar sensitivity and specificity to actigraphy for two-stage categorisation of sleep and can be used as a practical alternative to polysomnography for two-stage categorisation of sleep and four-stage categorisation of sleep.