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Background: The fecal immunochemical test (FIT) is widely used in colorectal cancer (CRC) screening, but limited data exist for its application in individuals at above-average risk for CRC who complete surveillance colonoscopies. Aim: To assess the accuracy, acceptability, and effectiveness of FIT in the interval between surveillance colonoscopies, for predicting advanced neoplasia (advanced adenoma or CRC) at the next colonoscopy. Methods: Individuals enrolled in an Australian surveillance program were included. Diagnostic accuracy was determined for 614 individuals completing a two-sample FIT (OC-Sensor) ≤ 3 months preceding surveillance colonoscopy. 386 Individuals were surveyed to assess acceptability of interval FIT. Additionally, a retrospective analysis was performed on 7331 individuals offered interval FIT between colonoscopies, where a positive FIT (≥ 20 µg hemoglobin/g feces) triggered an early colonoscopy. Associations between interval FIT results and advanced neoplasia were determined using regression analysis. Results: FIT detected CRC and advanced adenoma with sensitivities of 60.0% (3/5) and 27.1% (35/129), respectively. Most (89.1%, 344/386) survey respondents preferred completing interval FIT every 1–2 years. The detection rate of interval FIT for advanced neoplasia decreased with increasing FIT completion. Individuals returning a positive FIT had a higher risk of advanced neoplasia than those who did not complete FIT. Positive interval FIT reduced time-to-diagnosis for CRC and advanced adenoma by a median of 30 and 20 months, respectively. Conclusion: Interval FIT was well accepted and enabled earlier detection of advanced neoplasia in individuals at above-average risk of CRC. Given that interval FIT predicts advanced neoplasia, it may be used to personalize surveillance colonoscopy intervals. [ABSTRACT FROM AUTHOR]

Context: Evidence for declines in insect populations is growing with climate change being one suspected driver. Forests, however, are still underrepresented in the relevant research. Recent droughts (2018–2020) have severely affected forests in Central Europe and have been linked to declines in carabid abundance, biomass as well as changes in species traits at the local scale. Objective: We tested drought effects on forest carabids at regional scale. We additionally investigated whether variability in drought effects could be explained with the initial community composition and the local environmental context. Methods: We used generalized linear mixed models to compare data from 1999 to 2001 and 2020 to 2022 across eleven old beech forest sites of high conservation interest in North-East Germany and investigated changes in carabid abundance, biomass, Hill numbers and selected species traits. We then tested additional community-related and environmental predictors to explain spatial variability in changes in biomass. Results: We found significant declines in biomass of 65% and in abundance of 51%. There were no significant changes in Hill numbers. We found consistent evidence that declines affected especially larger and less mobile species. Declines and changes in species traits also occurred in strictly protected old-growth beech forests. Among environmental predictors, landscape composition explained local variability in biomass declines best with stronger decline at forest sites with less forest area in their vicinity. Conclusions: Our findings reveal large-scale declines in forest carabids in the context of recent droughts and highlight the exceptional role of landscape composition in this regard. Future insect conservation strategies need to incorporate the landscape context and potential exposure to extreme weather. [ABSTRACT FROM AUTHOR]

Background: Treatment of unresectable colorectal liver metastases (UCRLM) includes locoregional and systemic therapy. A comprehensive analysis capturing long-term outcomes of these treatment options has not been performed. Objective: A systematic review and meta-analysis was performed to calculate pooled outcomes of hepatic artery infusion with systemic chemotherapy (HAI-S), transarterial chemoembolization with systemic chemotherapy (TACE-S), transarterial radioembolization with systemic chemotherapy (TARE-S), doublet (FOLFOX, FOLFIRI), and triplet chemotherapy (FOLFOXIRI). Methods: Outcomes included overall survival (OS), progression-free survival (PFS), rate of conversion to resection (CTR), and response rate (RR). Results: A total of 32, 7, 9, and 14 publications were included in the HAI-S, TACE-S, and TARE-S chemotherapy arms. The 6/12/24/36-month OS estimates for HAI-S, TACE-S, TARE-S, FOLFOX, FOLFIRI, and FOLFOXIRI were 97%/80%/54%/35%, 100%/83%/40%/14%, 82%/61%/34%/21%, 96%/83%/53%/36%, and 96%/93%/72%/55%. Similarly, the 6/12/24/36-month PFS estimates were 74%/44%/19%/14%, 66%/20%/9%/3%, 57%/23%/10%/3%, 69%/30%/12%/7%, and 88%/55%/18%/11%. The corresponding CTR and RR rates were 31, 20%, unmeasurable (TARE-S), 35, 53; and 49, 45, 45, 50, 80%, respectively. The majority of chemotherapy studies included first-line therapy and liver-only metastases, whereas most HAI-S studies were pretreated. On subgroup analysis in first-line setting with liver-only metastases, the HAI-S arm had comparable outcomes to FOLFOXIRI and outperformed doublet chemotherapy regimens. Although triplet chemotherapy appeared to outperform other arms, high toxicity and inclusion of potentially resectable patients must be considered while interpreting results. Conclusions: HAI-S and multiagent chemotherapy are effective therapies for UCRLM. To make definitive conclusions, a randomized trial with comparable patient characteristics and line of therapy will be required. The upcoming EA2222 PUMP trial may help to address this question. [ABSTRACT FROM AUTHOR]

Upper hemi-sternotomy is a common approach for outflow graft anastomosis to the ascending aorta in minimally invasive left-ventricular assist device implantation. Right mini-thoracotomy may also be used, but use of robotic assistance has been reported only anecdotally. The aim of our study was to confirm the feasibility of robotically assisted suturing of the outflow graft anastomosis and to assess performance metrics for the robotic suturing part of the procedure. The procedure was carried out in eight cadaver studies by two surgeons. The assist device pump head was inserted through a left-sided mini-thoracotomy and the outflow graft was passed toward a right-sided second interspace mini-thoracotomy through the pericardium. After placement of a partial occlusion clamp on the ascending aorta, a longitudinal aortotomy was performed and the outflow graft to ascending aorta anastomosis was carried out robotically. The procedure was feasible in all eight attempts. The mean outflow graft anastomotic time was 20.1 (SD 6.8) min and the mean surgeon confidence and comfort levels to complete the anastomoses were 8.3 (SD 2.4) and 6.9 (SD2.2), respectively, on a ten-grade Likert scale. On open inspection of the anastomoses, there was good suture alignment in all cases. We conclude that suturing of a left-ventricular assist device outflow graft to the human ascending aorta is very feasible with good surgeon comfort. Anastomotic times are acceptable and suture placement can be performed with appropriate alignment. [ABSTRACT FROM AUTHOR]

The article announces the recipients of the 2023 DAC-EuChemS and Robert Kellner Award Lectures in analytical chemistry. Damià Barceló and Antje J. Baeumner received the awards for their research on microplastics in the aquatic environment and nanomaterials in biosensors, respectively. They discuss their motivations, research focus, and the importance of real-world applications and addressing environmental challenges. The article also covers topics such as biosensors, wearable and intelligent sensors, nucleic acid-based rapid tests, sample preparation strategies, and challenges in environmental analysis. It emphasizes the importance of proteomics in public health and mentions the identification of SARS-CoV-2 proteins in wastewater. The authors also discuss the pressure to publish in academia and offer advice to young scientists, while acknowledging the global impact of Chinese and Indian research. [Extracted from the article]

Complex oxides offer rich magnetic and electronic behavior intimately tied to the composition and arrangement of cations within the structure. Rare earth iron garnet films exhibit an anisotropy along the growth direction which has long been theorized to originate from the ordering of different cations on the same crystallographic site. Here, we directly demonstrate the three-dimensional ordering of rare earth ions in pulsed laser deposited (EuxTm1-x)3Fe5O12 garnet thin films using both atomically-resolved elemental mapping to visualize cation ordering and X-ray diffraction to detect the resulting order superlattice reflection. We quantify the resulting ordering-induced 'magnetotaxial' anisotropy as a function of Eu:Tm ratio using transport measurements, showing an overwhelmingly dominant contribution from magnetotaxial anisotropy that reaches 30 kJ m−3 for garnets with x = 0.5. Control of cation ordering on inequivalent sites provides a strategy to control matter on the atomic level and to engineer the magnetic properties of complex oxides. Magnetic anisotropy in mixed rare earth iron garnet films is shown to originate from the atomic ordering of the rare earth cations during growth of the film. Cation ordering on inequivalent sites provides a powerful strategy to engineer the magnetic properties of complex oxides. [ABSTRACT FROM AUTHOR]

Hikitia te Ora (Certificate in Health Sciences) is a 1 year Indigenous bridging foundation programme at the University of Auckland, Aotearoa New Zealand. The programme aims to increase Māori and Pacific health workforce representation. This qualitative study applied a Kaupapa Māori positioning to elucidate the strengths, challenges, and opportunities of the programme. Data were collected through two workshops and seven focus groups with a total of 67 participants who were students of Hikitia te Ora from past and present cohorts, or their family members. Using a general inductive thematic analysis, the primary themes identified were that programme successes encompassed whanaungatanga (process of establishing relationships), academic and pastoral support, programme structure and the teaching content. Challenges included social cliques and divisive social groupings, timetabling of courses and high workloads. The three areas that emerged for further development include extending Pacific content, increasing the number of students in the programme, and maintaining a programme-specific study space for students. Implementing the findings from this study into Hikitia te Ora is expected to improve educational outcomes for Māori and Pacific students and may have the potential to benefit other bridging foundation courses aiming to promote Indigenous health workforce development. [ABSTRACT FROM AUTHOR]

Objectives: This cross-sectional study aimed to determine the prevalence and risk factors for sleep-related breathing disorders (SRBD) in newly diagnosed, untreated rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients, and to develop a screening algorithm for early detection. Methods: We evaluated newly diagnosed RA or PsA patients using the Epworth Sleepiness Scale (ESS) questionnaire, cardiorespiratory polygraphy (RPG), and clinical and laboratory assessments. Sleep apnea syndrome (SAS) was diagnosed based on pathological RPG findings excessive daytime sleepiness, defined as ESS score above 10. Results: The study included 39 patients (22 RA, 17 PsA) and 23 controls. In RPG, SRBD was identified in 38.5% of arthritis patients compared to 39.1% of controls (p = 1.00), with male gender (p =.004) and age (p <.001) identified as risk factors. Excessive daytime sleepiness was noted in 36.4% of RA patients, 17.6% of PsA patients, and 21.7% of controls. Of the 24 patients diagnosed with SRBD, 41.6% met the criteria for SAS. SAS prevalence was 31.8% among RA patients, 0% in PsA patients, and 13% in controls. A significant association was observed between excessive daytime sleepiness and SRBD (p =.036). Conclusion: Our findings reveal a high prevalence of SRBD in newly diagnosed, untreated RA and PsA patients in ESS and RPG, with excessive daytime sleepiness being a reliable predictor of SRBD. Patients with RA exhibited a higher predisposition to SAS. We therefore suggest incorporating ESS and RPG as screening tools in RA or PsA for early detection and management of SRBD. [ABSTRACT FROM AUTHOR]

Copyright of Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

This document is a correction notice for an article published in the Journal of Neurology. It acknowledges an error in the original article where Table 1 was duplicated as Table 2. The correction provides the correct version of Table 2, which presents the results of a study comparing the use of 3T and 7T MRI in various neurological conditions. The study found that 7T MRI generally provided better visibility and delineation of structures compared to 3T MRI, but there were variations in the results depending on the specific condition being studied. [Extracted from the article]

Copyright of Wissen Kompakt is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: This qualitative study examines autistic adolescents' perception of the quality of their relationship with their parent using the Three Minute Speech Sample. Methods: Twenty autistic youth (13–17 years; 83% male) spoke, uninterrupted, for three minutes about their thoughts and feelings regarding their mothers. Audio-recorded speech samples were transcribed and coded for emergent themes. Results: Adolescents highlighted emotional support and acceptance in the context of their relationship, support mothers provide for mental health, love and caring, efforts to build the relationship through shared activities, and areas of adolescent-parent conflict. Conclusion: The TMSS is a low cost, low burden method by which autistic adolescents can comfortably and effectively self-report the quality of their relationship with their parent/caregiver. [ABSTRACT FROM AUTHOR]

Many collisions between pedestrians and cars are caused by poor visibility, such as occlusion by a parked vehicle. Augmented reality (AR) could help to prevent this problem, but it is unknown to what extent the augmented information needs to be embedded into the world. In this virtual reality experiment with a head-mounted display (HMD), 28 participants were exposed to AR designs, in a scenario where a vehicle approached from behind a parked vehicle. The experimental conditions included a head-locked live video feed of the occluded region, meaning it was fixed in a specific location within the view of the HMD (VideoHead), a world-locked video feed displayed across the street (VideoStreet), and two conformal diminished reality designs: a see-through display on the occluding vehicle (VideoSeeThrough) and a solution where the occluding vehicle has been made semi-transparent (TransparentVehicle). A Baseline condition without augmented information served as a reference. Additionally, the VideoHead and VideoStreet conditions were each tested with and without the addition of a guiding arrow indicating the location of the approaching vehicle. Participants performed 42 trials, 6 per condition, during which they had to hold a key when they felt safe to cross. The keypress percentages and responses from additional questionnaires showed that the diminished-reality TransparentVehicle and VideoSeeThrough designs came out most favourably, while the VideoHead solution caused some discomfort and dissatisfaction. An analysis of head yaw angle showed that VideoHead and VideoStreet caused divided attention between the screen and the approaching vehicle. The use of guiding arrows did not contribute demonstrable added value. AR designs with a high level of local embeddedness are beneficial for addressing occlusion problems when crossing. However, the head-locked solutions should not be immediately dismissed because, according to the literature, such solutions can serve tasks where a salient warning or instruction is beneficial. [ABSTRACT FROM AUTHOR]

Due to new requirements regarding the efficiency of electrical machines it is necessary to steadily improve machine concepts or create new ones. Therefore, manufacturing technology has to be continuously improved, adapted or developed new. Forming technology offers an excellent opportunity to implement components for highly efficient electrical machines through its advantages regarding high productivity and high degree of material usage. This paper presents a new method for bending complete stacks of grain oriented electric sheets for use as radially laminated modules in an innovative machine concept with flux barriers. First, the principle of electric drives with flux barriers and the arrangement of the new radial lamination are explained. Then, practical preliminary studies concerning the bending of single sheets are performed. Based on this, the process and tooling for bending of pre-stacked sheets is developed and analysed. Accordingly, an increase in material utilisation of about 30% can be expected compared to classically designed stators. Furthermore, the use of the radially laminated stator principle increases the slot area by about 20% which makes it possible to insert more copper into the slot and thus increase the efficiency of the machine during operation. After validation of the process chain with a demonstrator motor and description of several manufacturing and quality improvements, finally, an outlook is given, and possible further research approaches are discussed. [ABSTRACT FROM AUTHOR]

Purpose: Describe the process, outcomes, and costs of cancer registry recruitment and enrollment of sexual minority and heterosexual non-metastatic colorectal cancer survivors into an observational survivorship study. Methods: We recruited stage I–III colorectal cancer survivors from four US cancer registries. Potential participants were screened for eligibility, and all eligible sexual minority and every 10th heterosexual survivor was invited to participate in a 45-min telephone interview. Results: We mailed study packets to 17,855 individuals and obtained 6370 screening surveys of presumed eligible individuals. After screening, there were 182 eligible sexual minority and 5568 eligible heterosexual survivors. Of the 719 invited survivors, 127 sexual minority and 353 heterosexual individuals participated in the interview. There were some small differences in personal and neighborhood sociodemographic characteristics for the survivors who screened eligible and completed the interview relative to the registry sample. The per-participant direct costs were about $40, $120, and $1425 in the registry, screened eligible, and interviewed samples, respectively. Conclusions: Although we did not observe substantial selection biases, the costs of enrolling a representative sample were high. Implications for Cancer Survivors: Inclusion of sexual orientation and gender identity as standard demographic questions in cancer registries is needed for reliable and cost-efficient monitoring of population health. [ABSTRACT FROM AUTHOR]

The article discusses the rising use of e-cigarettes among teenagers in the Netherlands and its negative effects on their health. It highlights that e-cigarettes contain high doses of nicotine and other harmful chemicals, leading to adverse effects on stress levels, quality of life, and brain development in adolescents. The article also emphasizes that e-cigarettes serve as a gateway to traditional cigarette smoking, with two-thirds of adolescent e-cigarette users transitioning to smoking tobacco. The authors call for government-led initiatives, such as taxation and banning e-cigarettes, along with health education targeting adolescents to address the vaping epidemic. In the Netherlands, physicians have taken action by developing educational materials and offering guest lectures in schools to raise awareness about the risks of e-cigarettes. The article concludes by emphasizing the importance of healthcare providers and the government working together to protect young people from the tobacco industry and prevent disease. [Extracted from the article]

Copyright of Zeitschrift für Erziehungswissenschaft is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We present a complete classification of the geometry of the mutually complementary sets of entangled and separable states in three-dimensional Hilbert subspaces of bipartite and multipartite quantum systems. Our analysis begins by finding the geometric structure of the pure product states in a given three-dimensional Hilbert subspace, which determines all the possible separable and entangled mixed states over the same subspace. In bipartite systems, we characterise the 14 possible qualitatively different geometric shapes for the set of separable states in any three-dimensional Hilbert subspace (5 classes which also appear in two-dimensional subspaces and were found and analysed by Boyer et al. (Phys Rev A 95:032308, 2017. ), and 9 novel classes which appear only in three-dimensional subspaces), describe their geometries, and provide figures illustrating them. We also generalise these results to characterise the sets of fully separable states (and hence the complementary sets of somewhat entangled states) in three-dimensional subspaces of multipartite systems. Our results show which geometrical forms quantum entanglement can and cannot take in low-dimensional subspaces. [ABSTRACT FROM AUTHOR]

We provide a general expression of the Haar measure—that is, the essentially unique translation-invariant measure—on a p-adic Lie group. We then argue that this measure can be regarded as the measure naturally induced by the invariant volume form on the group, as it happens for a standard Lie group over the reals. As an important application, we next consider the problem of determining the Haar measure on the p-adic special orthogonal groups in dimension two, three and four (for every prime number p). In particular, the Haar measure on SO (2 , Q p) is obtained by a direct application of our general formula. As for SO (3 , Q p) and SO (4 , Q p) , instead, we show that Haar integrals on these two groups can conveniently be lifted to Haar integrals on certain p-adic Lie groups from which the special orthogonal groups are obtained as quotients. This construction involves a suitable quaternion algebra over the field Q p and is reminiscent of the quaternionic realization of the real rotation groups. Our results should pave the way to the development of harmonic analysis on the p-adic special orthogonal groups, with potential applications in p-adic quantum mechanics and in the recently proposed p-adic quantum information theory. [ABSTRACT FROM AUTHOR]

Chronic nonbacterial osteitis (CNO) is a rare musculoskeletal disease causing chronic bone pain. It is known that chronic musculoskeletal pain may involve other mechanisms than nociceptive pain only. We investigate the prevalence of neuropathic and nociplastic pain in adult CNO and their association with clinical characteristics and treatment outcomes. Survey study among the Dutch adult CNO cohort (n = 84/195 participated), including PAIN-detect for neuropathic pain, and the Central Sensitization Inventory (CSI), Fibromyalgia Rapid Screening Tool (FiRST), and ACTTION-APS Pain Taxonomy (AAPT) for nociplastic pain. Clinical characteristics and CNO-related bone pain scores were compared between patients with exclusive nociceptive pain and those with nociceptive pain plus neuropathic and/or nociplastic pain (mixed pain). 31% (95% CI 21–41) of patients classified as likely having neuropathic pain according to PAIN-detect. 53% (41–64) of patients displayed central sensitization on CSI, 61% (50–72) screened positive for fibromyalgia on FiRST and 14% (7–23) of patients fulfilled the AAPT criteria, all indicative of nociplastic pain. Mixed pain was associated with longer diagnostic delay (mean difference 2.8 years, 95% CI 0.4–5.2, p = 0.023), lower educational level (72% versus 20%, p < 0.001), and opioid use (37% versus 13%, p = 0.036). Despite comparable disease severity and extent, patients with mixed pain reported significantly higher CNO-related bone pain scores. This study demonstrates the high prevalence of mixed pain in adult CNO, in which neuropathic and nociplastic pain exist alongside nociceptive inflammatory bone pain. Disease burden in CNO may extend beyond inflammatory activity, highlighting the need for a multifaceted management approach. [ABSTRACT FROM AUTHOR]

Purpose: This umbrella review aimed to critically appraise the evidence published in systematic reviews (SRs) on the clinical effectiveness of sealants compared with each other/the non-use in primary/permanent teeth of children and adolescents with at least 12-month follow-up. Methods: A systematic literature search on 4 electronic databases was conducted up to January 18th, 2023. Following handsearching, two review authors independently screened retrieved articles, extracted data, and assessed the risk of bias (RoB) using the risk of bias in systematic reviews (ROBIS) tool. Based on a citation matrix, the overlap was interpreted by the corrected covered area (CCA). Results: Of 239 retrieved records, 7 SRs met the eligibility criteria with a moderate overlap among them (CCA = 7.4%). For primary molars, in 1120 1.5- to 8-year-old children, data on the clinical effectiveness of sealants were inconclusive. For permanent molars, 3 SRs found a significant caries risk reduction for sealants versus non-use (≤ 36-month follow-up). There was insufficient evidence to proof superiority of sealants over fluoride varnish for caries prevention (3 SRs), and to rank sealant materials according to the best clinical effectiveness in permanent molars. One study was rated at low and 6 at high RoB, which did not allow for a valid quantitative synthesis. Conclusion: Considering the limitations of this umbrella review, sealants are more effective for caries prevention in children's permanent molars compared to no treatment. Future well-implemented RCTs are needed to draw reliable conclusions on the clinical effectiveness of sealants in primary and permanent teeth of children and adolescents. [ABSTRACT FROM AUTHOR]

Intracranial aneurysms (IAs) are present in 2–6% of the global population and can be catastrophic upon rupture with a mortality rate of 30–50%. IAs are commonly detected through time-of-flight magnetic resonance angiography (TOF-MRA), however, this data is rarely available for research and training purposes. The provision of imaging resources such as TOF-MRA images is imperative to develop new strategies for IA detection, rupture prediction, and surgical training. To support efforts in addressing data availability bottlenecks, we provide an open-access TOF-MRA dataset comprising 63 patients, of which 24 underwent interval surveillance imaging by TOF-MRA. Patient scans were evaluated by a neuroradiologist, providing aneurysm and vessel segmentations, clinical annotations, 3D models, in addition to 3D Slicer software environments containing all this data for each patient. This dataset is the first to provide interval surveillance imaging for supporting the understanding of IA growth and stability. This dataset will support computational and experimental research into IA dynamics and assist surgical and radiology training in IA treatment. [ABSTRACT FROM AUTHOR]

Proteins delivered by endocytosis or autophagy to lysosomes are degraded by exo- and endoproteases. In humans 15 lysosomal cathepsins (CTS) act as important physiological regulators. The cysteine proteases CTSB and CTSL and the aspartic protease CTSD are the most abundant and functional important lysosomal proteinases. Whereas their general functions in proteolysis in the lysosome, their individual substrate, cleavage specificity, and their possible sequential action on substrate proteins have been previously studied, their functional redundancy is still poorly understood. To address a possible common role of highly expressed and functional important CTS proteases, we generated CTSB-, CTSD-, CTSL-, and CTSBDL-triple deficient (KO) human neuroblastoma-derived SH-SY5Y cells and CTSB-, CTSD-, CTSL-, CTSZ and CTSBDLZ-quadruple deficient (KO) HeLa cells. These cells with a combined cathepsin deficiency exhibited enlarged lysosomes and accumulated lipofuscin-like storage material. The lack of the three (SH-SY5Y) or four (HeLa) major CTSs caused an impaired autophagic flux and reduced degradation of endocytosed albumin. Proteome analyses of parental and CTS-depleted cells revealed an enrichment of cleaved peptides, lysosome/autophagy-associated proteins, and potentially endocytosed membrane proteins like the amyloid precursor protein (APP), which can be subject to endocytic degradation. Amino- and carboxyterminal APP fragments accumulated in the multiple CTS-deficient cells, suggesting that multiple CTS-mediated cleavage events regularly process APP. In summary, our analyses support the idea that different lysosomal cathepsins act in concert, have at least partially and functionally redundant substrates, regulate protein degradation in autophagy, and control cellular proteostasis, as exemplified by their involvement in the degradation of APP fragments. [ABSTRACT FROM AUTHOR]

Within a year of its launch, ChatGPT has seen a surge in popularity. While many are drawn to its effectiveness and user-friendly interface, ChatGPT also introduces moral concerns, such as the temptation to present generated text as one's own. This led us to theorize that personality traits such as Machiavellianism and sensation-seeking may be predictive of ChatGPT usage. We launched two online questionnaires with 2000 respondents each, in September 2023 and March 2024, respectively. In Questionnaire 1, 22% of respondents were students, and 54% were full-time employees; 32% indicated they used ChatGPT at least weekly. Analysis of our ChatGPT Acceptance Scale revealed two factors, Effectiveness and Concerns, which correlated positively and negatively, respectively, with ChatGPT use frequency. A specific aspect of Machiavellianism (manipulation tactics) was found to predict ChatGPT usage. Questionnaire 2 was a replication of Questionnaire 1, with 21% students and 54% full-time employees, of which 43% indicated using ChatGPT weekly. In Questionnaire 2, more extensive personality scales were used. We found a moderate correlation between Machiavellianism and ChatGPT usage (r = 0.22) and with an opportunistic attitude towards undisclosed use (r = 0.30), relationships that largely remained intact after controlling for gender, age, education level, and the respondents' country. We conclude that covert use of ChatGPT is associated with darker personality traits, something that requires further attention. [ABSTRACT FROM AUTHOR]

Polyurethane (PU) is a versatile polymer with many applications in a wide range of products. A novel 3D printing technology called liquid additive manufacturing (LAM) extended its possibilities by generating PU elastomers with gradient properties in continuous processing. LAM, being a relatively new technique, has not been extensively researched, particularly in terms of the curing behavior of the liquid resin. In this work, we investigated the effect of composition on gelation time tGP as measured by time-resolved mechanical spectroscopy (TRMS) and analyzed using the Winter–Chambon criterion with the assistance of the IRIS software. This method is more accurate than the previous approach, which involved time sweeps with a constant frequency. It was found that the gel time tGP first decreased and then increased with increasing polyol ratio, ranging from 231 to 378 min. Furthermore, the crosslink densities of the different PU elastomers measured from the rheological and tensile tests were calculated and compared based on the theory of rubber elasticity. The crosslink density decreased with an increasing polyol ratio in both methods. However, the crosslink density values obtained from the rheological measurements were higher than those from the tensile tests. These findings demonstrate that adjusting the polyol ratio is an effective means of achieving gradient properties. The composition effects we measured offer valuable insights for the design of LAM–PU elastomers. [ABSTRACT FROM AUTHOR]

Railway infrastructure maintenance faces a challenge posed by the laborious task of monitoring widespread deformation, which is critical for ensuring safety. This study utilized the Persistent Scatterer Interferometric Synthetic Aperture Radar (PS-InSAR) technique with high-resolution TerraSAR-X satellite images to measure and analyze deformation at the operating track. Tailored through parameter optimization to fit regional topography and validated against field measurements, PS-InSAR was applied across a 30km by 50km area over two years. The analysis demonstrated that PS-InSAR could efficiently generate high-accuracy time-series data, capable of detecting both the uplift and subsidence processes. It highlighted the importance of augmenting single-point subsidence values with comprehensive time-series analysis for a complete deformation assessment. The study concluded that PS-InSAR is an accurate and cost-effective tool for large-scale linear infrastructure monitoring, despite technological constraints such as radar imaging frequency and the lack of high-resolution sources. Consideringthese constraints, future research will prioritize developing an enhanced algorithm capable of analyzing both urban and suburban areas, accommodating varying numbers of point scatterers. [ABSTRACT FROM AUTHOR]

Neurological conditions are the leading cause of disability and mortality combined, demanding innovative, scalable, and sustainable solutions. Brain health has become a global priority with adoption of the World Health Organization's Intersectoral Global Action Plan in 2022. Simultaneously, rapid advancements in artificial intelligence (AI) are revolutionizing neurological research and practice. This scoping review of 66 original articles explores the value of AI in neurology and brain health, systematizing the landscape for emergent clinical opportunities and future trends across the care trajectory: prevention, risk stratification, early detection, diagnosis, management, and rehabilitation. AI's potential to advance personalized precision neurology and global brain health directives hinges on resolving core challenges across four pillars—models, data, feasibility/equity, and regulation/innovation—through concerted pursuit of targeted recommendations. Paramount actions include swift, ethical, equity-focused integration of novel technologies into clinical workflows, mitigating data-related issues, counteracting digital inequity gaps, and establishing robust governance frameworks balancing safety and innovation. [ABSTRACT FROM AUTHOR]

Background: To specify peripheral nerve affection in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) by correlating high-resolution nerve ultrasound and nerve conduction studies. Methods: We assessed a cohort of 11 ARSACS patients with standardized nerve conduction studies and high-resolution ultrasound of peripheral nerves and compared nerve ultrasound findings to a healthy control group matched for age, sex, size and weight. Results: Mean age of patients was 39.0 (± 14.1) years and disease duration at assessment 30.6 (± 12.5) years. All patients presented with a spasticity, ataxia and peripheral neuropathy. Neuropathy appeared to be primarily demyelinating in 9/11 cases and was not classifiable in 2/11 cases due to not evocable potentials. Nerve ultrasound revealed a normal ultrasound pattern sum score (UPSS) in each ARSACS patient and no significant nerve enlargement compared to the control group. Conclusions: Peripheral neuropathy in ARSACS showed primarily demyelinating rather than axonal characteristics and presented without nerve enlargement. As demyelinating neuropathies do commonly present enlarged nerves we recommend further genetic testing of the SACS gene in patients who present with this combination of demyelinating neuropathy without nerve enlargement. ARSACS cases that initially presented only with neuropathy without spasticity or ataxia and therefore were misdiagnosed as Charcot-Marie-Tooth disease are supporting this suggestion. [ABSTRACT FROM AUTHOR]

There is high market demand for increasing the viability of current plastic recycling processes. In this work rheology is used to evaluate the mechanical properties of a solvent dissolution recycled polymer compared to its virgin untreated precursor. Solvent dissolution and precipitation are used to target multi-layer, multi-component, industry films, which cannot be mechanically recycled. Polyethylene was chosen as the primary polymer of interest. Polymer thermal stability was monitored via time-resolved rheology; consecutive frequency sweeps over the course of an hour while under isothermal conditions. Additional rheological experiments were performed within the identified thermally stable conditions. Small-angle oscillatory shear was complemented with steady shear viscosity experiments over a wide range of shear rates. Extensional rheology was used to determine changes in molecular weight and cross link density. Rheological characterization is supplemented with gas chromatography–mass spectrometry of the solvent wash to determine components stripped from the virgin polymers during solvent treatment. [ABSTRACT FROM AUTHOR]

Purpose: Statins are commonly prescribed medications with recognised side effects including muscle weakness. Despite this, little is known about their effect on the physical activity and falls risk in the older population. This paper aims to explore the relationship between statin use and the physical activity and falls risk in adults aged 65 and older. Methods: MEDLINE, Embase, CINAHL and PsycINFO were searched on 21/11/2022 to obtain relevant articles. Data considered appropriate included that relating to muscle strength, grip strength, gait speed, balance and falls incidence. Reference and citation searches were performed to identify further relevant papers, and all eligible articles were subject to a Critical Appraisal Skills Programme (CASP) to assess potential bias. With the data being highly heterogeneous, no attempt to measure effect size was made and a narrative synthesis approach was used. The review proposal was registered with PROSPERO: CRD42022366159. Results: Twenty articles were included. Data were inconsistent throughout, with the overall trend suggesting no significant negative effects of statins on the parameters of physical activity, or on falls risk. This was especially true in matched and adjusted cohorts, where potential confounders had been accounted for. Conclusion: This review did not identify a relationship between statin use and physical activity and falls risk in people aged 65 years and older. Ultimately, the risks and benefits of every medication should be considered in the context of each individual. [ABSTRACT FROM AUTHOR]

Abstract Durable cell‐mediated immune responses require efficient innate immune signaling and the release of pro‐inflammatory cytokines. How precisely mRNA vaccines trigger innate immune cells for shaping antigen specific adaptive immunity remains unknown. Here, we show that SARS‐CoV‐2 mRNA vaccination primes human monocyte‐derived macrophages for activation of the NLRP3 inflammasome. Spike protein exposed macrophages undergo NLRP3‐driven pyroptotic cell death and subsequently secrete mature interleukin‐1β. These effects depend on activation of spleen tyrosine kinase (SYK) coupled to C‐type lectin receptors. Using autologous cocultures, we show that SYK and NLRP3 orchestrate macrophage‐driven activation of effector memory T cells. Furthermore, vaccination‐induced macrophage priming can be enhanced with repetitive antigen exposure providing a rationale for prime‐boost concepts to augment innate immune signaling in SARS‐CoV‐2 vaccination. Collectively, these findings identify SYK as a regulatory node capable of differentiating between primed and unprimed macrophages, which modulate spike protein‐specific T cell responses.

We consider a simplified model to study some types of elongated asteroids with three protuberances, two at the ends and one in the middle. An example considered in this work is the asteroid Holiday. To model these bodies, we consider a tripolar system with a segment, which consists of a massive segment and three spheres, two at the ends of the segment and one between them, rotating around their center of mass with uniform angular velocity. In particular, we restrict our case to variations in masses and their positions, as well as variations in the mass of the segment or rod. For this problem, we obtain the potential and calculate families of symmetric periodic orbits, analyzing asymptotic points that may represent heteroclinic orbits as well as orbits that may represent possible collisions with the studied body. Furthermore, it was possible to obtain zero velocity curves and equilibrium points of the system. The analysis of symmetric periodic orbits can contribute to improve the efficiency of space missions, prolonging the useful life of satellites or spacecraft, in addition to collaborating for a better understanding of the dynamics of a satellite around an asteroid. The asteroid Holiday was chosen due to its degree of importance, both for its proximity to our planet and its periodicity, which led NASA to classify it as potentially dangerous. [ABSTRACT FROM AUTHOR]

This document is a collection of biographical profiles of contributors to the Advances in (Bio-)Analytical Chemistry: Reviews and Trends Collection 2024. The collection features review-type articles by the journal's Editorial Board, showcasing their expertise in various areas of analytical chemistry. The contributors include researchers from institutions around the world, such as the University of Regensburg, Peking University, the University of North Carolina at Chapel Hill, and the University of Oviedo. Their research interests range from biosensors and nanotechnology to mass spectrometry and electrochemical analysis. These profiles provide valuable insights into the diverse perspectives and accomplishments of these researchers in the field of analytical chemistry. [Extracted from the article]

Individual-level assessment of health and well-being permits analysis of community well-being and health risk evaluations across several dimensions of health. It also enables comparison and rankings of reported health and well-being for large geographical areas such as states, metropolitan areas, and counties. However, there is large variation in reported well-being within such large spatial units underscoring the importance of analyzing well-being at more granular levels, such as ZIP codes. In this paper, we address this problem by modeling well-being data to generate ZIP code tabulation area (ZCTA)-level rankings through spatially informed statistical modeling. We build regression models for individual-level overall well-being index and scores from five subscales (Physical, Financial, Social, Community, Purpose) using individual-level demographic characteristics as predictors while including a ZCTA-level spatial effect. The ZCTA neighborhood information is incorporated by using a graph Laplacian matrix; this enables estimation of the effect of a ZCTA on well-being using individual-level data from that ZCTA as well as by borrowing information from neighboring ZCTAs. We deploy our model on well-being data for the U.S. states of Massachusetts and Georgia. We find that our model can capture the effects of demographic features while also offering spatial effect estimates for all ZCTAs, including ones with no observations, under certain conditions. These spatial effect estimates provide community health and well-being rankings of ZCTAs, and our method can be deployed more generally to model other outcomes that are spatially dependent as well as data from other states or groups of states. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA–IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA–IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells.IL-27RA–IL-27 has a critical role in the immunity to EBV, and this defence is hijacked by Epstein–Barr virus to promote the expansion of infected transformed B cells [ABSTRACT FROM AUTHOR]

Background: Childhood cancer survivors are at risk of subsequent gliomas and meningiomas, but the risks beyond age 40 years are uncertain. We quantified these risks in the largest ever cohort. Methods: Using data from 69,460 5-year childhood cancer survivors (diagnosed 1940–2008), across Europe, standardized incidence ratios (SIRs) and cumulative incidence were calculated. Results: In total, 279 glioma and 761 meningioma were identified. CNS tumour (SIR: 16.2, 95% CI: 13.7, 19.2) and leukaemia (SIR: 11.2, 95% CI: 8.8, 14.2) survivors were at greatest risk of glioma. The SIR for CNS tumour survivors was still 4.3-fold after age 50 (95% CI: 1.9, 9.6), and for leukaemia survivors still 10.2-fold after age 40 (95% CI: 4.9, 21.4). Following cranial radiotherapy (CRT), the cumulative incidence of a glioma in CNS tumour survivors was 2.7%, 3.7% and 5.0% by ages 40, 50 and 60, respectively, whilst for leukaemia this was 1.2% and 1.7% by ages 40 and 50. The cumulative incidence of a meningioma after CRT in CNS tumour survivors doubled from 5.9% to 12.5% between ages 40 and 60, and in leukaemia survivors increased from 5.8% to 10.2% between ages 40 and 50. Discussion: Clinicians following up survivors should be aware that the substantial risks of meningioma and glioma following CRT are sustained beyond age 40 and be vigilant for symptoms. [ABSTRACT FROM AUTHOR]

The First 1000 Days (the period from conception to a child's second birthday) is an important developmental period. However, little is known about experiences of parents with refugee and migrant backgrounds during this period. A systematic review was conducted according to PRISMA guidelines. Publications were identified through searches of the Embase, PsycINFO, PubMed, and Scopus databases, critically appraised, and synthesised using thematic analysis. A total of 35 papers met inclusion criteria. Depressive symptomatology was consistently higher than global averages, however maternal depression conceptualisations differed across studies. Several papers reported changes in relationship dynamics as a result of having a baby post-migration. Consistent relationships were found between social and health support and wellbeing. Conceptualisations of wellbeing may differ among migrant families. Limited understanding of health services and relationships with health providers may impede help-seeking. Several research gaps were identified, particularly in relation to the wellbeing of fathers, and of parents of children over 12 months old. [ABSTRACT FROM AUTHOR]

A (convex) polytope P ⊂ R d and its edge-graph G P can have very distinct symmetry properties, in that the edge-graph can be much more symmetric than the polytope. In this article we ask whether this can be "rectified" by coloring the vertices and edges of G P , that is, whether we can find such a coloring so that the combinatorial symmetry group of the colored edge-graph is actually isomorphic (in a natural way) to the linear or orthogonal symmetry group of the polytope. As it turns out, such colorings exist and some of them can be constructed quite naturally. However, actually proving that they "capture polytopal symmetries" involves applying rather unexpected techniques from the intersection of convex geometry and spectral graph theory. [ABSTRACT FROM AUTHOR]

Recently, we have seen a series of space missions to the Moon and asteroids, whether for exploratory or scientific purposes, with possibilities of a lot of profitability in a sustainable way. Given this scenario, the Garatéa-L Mission (from the Brazilian original people language Tupi-Guarani, "Search for Life") stands out, a genuinely Brazilian mission, whose main objective is to place a 6U brazilian cubeSat in orbit around the Moon, in 2024 or 2025, with the aim of carrying out experiments in astrobiology and studying the Aitken Basin, a basin located at the lunar south pole. In this context, the main goal of the present work is to study the orbits that meet the needs of the mission, obeying the necessary parameters of 300 km of periselene and 3000 km of aposelene. The system is formed by the Moon (the central body) and its gravitational coefficients, J 2 , J 3 and C 22 , the Earth as the perturbing body and a particle (cubesat). As a result, we obtained a sample of orbits that meets the requirements of the mission, their lifetimes in the region of interest and the evolution of the semi-major axis and eccentricity for each value of the inclination analysed. The results showed that the largest number of orbits with the longest lifetime have inclinations of 60° and 65°, with a semi-major axis of 3460 km and an eccentricity of approximately 0.38, remaining in the mission's region of interest for an approximate period of 180 days. [ABSTRACT FROM AUTHOR]

Approximately one half of patients with non-small cell lung cancer (NSCLC) are diagnosed at resectable tumor stages (I-IIIA), which can potentially be curatively treated. In the early tumor stages (tumor diameter ≤2 cm) sublobar resection (segmentectomy or atypical wedge resection) leads to a 5‑year long-term survival comparable to lobectomy. The use of immunotherapy, especially within the framework of neoadjuvant treatment, is anticipated to change the surgical treatment of NSCLC in the future. With the introduction of lung cancer screening for certain risk groups in Germany planned for 2024, lung tumors can be expected to be diagnosed at earlier stages and more frequently curatively treated. This article provides an overview of the potential impact of lung cancer screening, modern minimally invasive surgical techniques and neoadjuvant treatment concepts for the surgical treatment of NSCLC. [ABSTRACT FROM AUTHOR]

For a class of aggregation models on the integer lattice Z d , d ≥ 2 , in which clusters are formed by particles arriving one after the other and sticking irreversibly where they first hit the cluster, including the classical model of diffusion-limited aggregation (DLA), we study the growth of the clusters. We observe that a method of Kesten used to obtain an almost sure upper bound on the radial growth in the DLA model generalizes to a large class of such models. We use it in particular to prove such a bound for the so-called ballistic model, in which the arriving particles travel along straight lines. Our bound implies that the fractal dimension of ballistic aggregation clusters in Z 2 is 2, which proves a long standing conjecture in the physics literature. [ABSTRACT FROM AUTHOR]

Viticulture is an example of a socio-ecological system that poses serious challenges for sustainable soil management and pesticide use, with various interactions between winegrowers' decision-making and ecological consequences. This study introduces an agent-based model (ABM) on winegrowers' decision on inter-row management and pesticide use. The ABM builds upon an empirical study of winegrowers' decision-making in European viticultural landscapes and has been built for three case study regions: Leithaberg (Austria), Palatinate (Germany) and Târnave (Romania). The ABM allows for analysing potential effects of policy instruments including mandatory vegetation cover in the inter-rows, the reduction of fungicide use and ban of insecticides against Lobesia botrana. The effects of policies differ between the case study regions, indicating how important the local context is for effective policies. For example, policies aiming at higher inter-row vegetation cover had the strongest effects on vegetation cover, landscape aesthetics and soil loss in Târnave since many vineyards are currently intensively tilled and there exist no policies supporting inter-row vegetation cover in Romania. Highlights: We introduce an agent-based model suite for three European winegrowing regions. The model explores vegetation and pest management and their ecological consequences. The feedback loop between decision-making and ecological processes is closed. Each region is simulated under climate change and various policy instruments. Results show that context is important for effective policies. [ABSTRACT FROM AUTHOR]

Arteriovenous malformations (AVMs) are vascular malformations of the central nervous system (CNS) with potential for significant consequences. The exact pathophysiologic mechanism of AVM formation is not fully understood. This study aims to evaluate bibliometric parameters and citations of the literature of AVMs to provide an overview of how the field has evolved. We performed an electronic search on Web of Science to identify the top 100 published and indexed articles with the highest number of citations discussing the pathogenesis of AVMs. This study yielded 1863 articles, of which the top 100 were selected based on the highest total citation count. These articles included 24% basic science, 46% clinical, and 30% review articles. The most-cited article was a clinical article from 2003, and the most recent was published in 2022. The median number of authors was 6, with the highest being 46 for a clinical article. The top 5 journals were identified, with the highest impact factor being 20.1. 13 countries were identified, with the US contributing the most articles (approximately 70%). Regarding genes of investigation, VEGF was one of the early genes investigated, while more interested in RAS/MAPK has been garnered since 2015. There is a growing interest in AVM genomics and pathogenesis research. While progress has been made in understanding clinical aspects and risk factors, the exact pathophysiological mechanisms and genetic basis of AVM formation remain incompletely understood. Further investigation of key genes in AVM pathogenesis can allow identification of potential therapeutic targets. [ABSTRACT FROM AUTHOR]

This study explores the potential of ChatGPT, a large language model, in scientometrics by assessing its ability to predict citation counts, Mendeley readers, and social media engagement. In this study, 2222 abstracts from PLOS ONE articles published during the initial months of 2022 were analyzed using ChatGPT-4, which used a set of 60 criteria to assess each abstract. Using a principal component analysis, three components were identified: Quality and Reliability, Accessibility and Understandability, and Novelty and Engagement. The Accessibility and Understandability of the abstracts correlated with higher Mendeley readership, while Novelty and Engagement and Accessibility and Understandability were linked to citation counts (Dimensions, Scopus, Google Scholar) and social media attention. Quality and Reliability showed minimal correlation with citation and altmetrics outcomes. Finally, it was found that the predictive correlations of ChatGPT-based assessments surpassed traditional readability metrics. The findings highlight the potential of large language models in scientometrics and possibly pave the way for AI-assisted peer review. [ABSTRACT FROM AUTHOR]

The clinical use of therapeutic monoclonal antibodies (mAbs) for the treatment of cancer, inflammation, and other indications has been successfully established. A critical aspect of drug-antibody pharmacokinetics is immunogenicity, which triggers an immune response via an anti-drug antibody (ADA) and forms drug/ADA immune complexes (ICs). As a consequence, there may be a reduced efficacy upon neutralization by ADA or an accelerated drug clearance. It is therefore important to understand immunogenicity in biological therapies. A drug-like immunoglobulin G (IgG) was radiolabeled with tritium, and ICs were formed using polyclonal ADA, directed against the complementary-determining region of the drug-IgG, to investigate in vivo biodistribution in rodents. It was demonstrated that 65% of the radioactive IC dose was excreted within the first 24 h, compared with only 6% in the control group who received non-complexed 3H-drug. Autoradiographic imaging at the early time point indicated a deposition of immune complexes in the liver, lung, and spleen indicated by an increased radioactivity signal. A biodistribution study confirmed the results and revealed further insights regarding excretion and plasma profiles. It is assumed that the immune complexes are readily taken up by the reticuloendothelial system. The ICs are degraded proteolytically, and the released radioactively labeled amino acids are redistributed throughout the body. These are mainly renally excreted as indicated by urine measurements or incorporated into protein synthesis. These biodistribution studies using tritium-labeled immune complexes described in this article underline the importance of understanding the immunogenicity induced by therapeutic proteins and the resulting influence on biological behavior. Created with BioRender.com [ABSTRACT FROM AUTHOR]

Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)—bifunctional compounds composed of two separate moieties that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target1–4. Here, using orthogonal genetic screening, biophysical characterization and structural reconstitution, we investigate the mechanism of action of bifunctional degraders of BRD2 and BRD4, termed intramolecular bivalent glues (IBGs), and find that instead of connecting target and ligase in trans as PROTACs do, they simultaneously engage and connect two adjacent domains of the target protein in cis. This conformational change ‘glues’ BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic target–ligase affinities that do not translate to BRD4 degradation in the absence of compound. Structural insights into the ternary BRD4–IBG1–DCAF16 complex guided the rational design of improved degraders of low picomolar potency. We thus introduce a new modality in targeted protein degradation, which works by bridging protein domains in cis to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation.Studies using genetic screening, biophysical characterization and structural reconstitution elucidate the mechanism of action and enable rational design of a new class of functional compounds that glue target proteins to E3 ligases via intramolecularly bridging two domains to enhance intrinsic protein–protein interactions and promote target ubiquitination and degradation. [ABSTRACT FROM AUTHOR]

Iconic words and signs are characterized by a perceived resemblance between aspects of their form and aspects of their meaning. For example, in English, iconic words include peep and crash, which mimic the sounds they denote, and wiggle and zigzag, which mimic motion. As a semiotic property of words and signs, iconicity has been demonstrated to play a role in word learning, language processing, and language evolution. This paper presents the results of a large-scale norming study for more than 14,000 English words conducted with over 1400 American English speakers. We demonstrate the utility of these ratings by replicating a number of existing findings showing that iconicity ratings are related to age of acquisition, sensory modality, semantic neighborhood density, structural markedness, and playfulness. We discuss possible use cases and limitations of the rating dataset, which is made publicly available. [ABSTRACT FROM AUTHOR]