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Aim: We are using the fossil record of different marine plankton groups to determine how their biodiversity has changed during past climate warming comparable to projected future warming. Location: North Atlantic Ocean and adjacent seas. Time series cover a latitudinal range from 75° N to 6° S. Time period: Past 24,000 years, from the Last Glacial Maximum (LGM) to the current warm period covering the last deglaciation. Major taxa studied: Planktonic foraminifera, dinoflagellates and coccolithophores. Methods: We analyse time series of fossil plankton communities using principal component analysis and generalized additive models to estimate the overall trend of temporal compositional change in each plankton group and to identify periods of significant change. We further analyse local biodiversity change by analysing species richness, species gains and losses, and the effective number of species in each sample, and compare alpha diversity to the LGM mean. Results: All plankton groups show remarkably similar trends in the rates and spatio‐temporal dynamics of local biodiversity change and a pronounced non‐linearity with climate change in the current warm period. Assemblages of planktonic foraminifera and dinoflagellates started to change significantly with the onset of global warming around 15,500 to 17,000 years ago and continued to change at the same rate during the current warm period until at least 5000 years ago, while coccolithophore assemblages changed at a constant rate throughout the past 24,000 years, seemingly irrespective of the prevailing temperature change. Main conclusions: Climate change during the transition from the LGM to the current warm period led to a long‐lasting reshuffling of zoo‐ and phytoplankton assemblages, likely associated with the emergence of new ecological interactions and possibly a shift in the dominant drivers of plankton assemblage change from more abiotic‐dominated causes during the last deglaciation to more biotic‐dominated causes with the onset of the Holocene. [ABSTRACT FROM AUTHOR]

A material flow model for the production of Bifacial Selective Emitter 60-cell p-type Cz PERC (Passivated Emitter and Rear Contacted) glass-backsheet modules with aluminium frame was built. The selected module represents mature technologies in the PV industry and their manufacturing is considered to take place in China in a production cluster with an annual module capacity of 5 GWp. In a first step, data acquisition and validation for wafer, cell and module fabs took place. The data were used to generate the reference system lifecycle inventories (LCI) and extended waste databases for the reference wafers, cells and modules. A set of potential circularity actions, such as the vertical integration of the operations and waste revalorisation strategies, had been proposed and their environmental performance and cost assessed by means of a life cycle assessment (LCA) and a total cost of ownership (TCO). Our results show that 87% of the waste can be reduced and revalorised, this represents a circular flow of raw materials of 18,756 Mg per year from a 5GWp PV module production cluster. Environmental impact reductions of 0.6–2.3% are estimated for different impact categories. We also estimate a cost reduction potential of 2.59% from total module costs.

Introduction: Because MRGPRX2 is now recognized as the mast cell receptor for basic secretagogues, there is currently a tremendous interest in whether MRGRPX2 could play an important role in various pruritic dermatoses such as chronic spontaneous urticaria. Therefore, we sought to identify new potent and selective antagonists to pharmacologically characterize the biological role of MRGPRX2., Methods: Various relevant in vitro , ex vivo , and in vivo model systems were used to investigate the role of MRGPRX2. This included the study of freshly isolated human skin mast cells and human basophils as well as an ex vivo human skin microdialysis preparation. The additivity of MRGPRX2 and FcεR1-mediated degranulation was also investigated. Human MRGPRX2 knock-in mice were generated to interrogate pharmacokinetic/pharmacodynamic relationships because both antagonists studied were shown to be human specific., Results: Two novel and structurally distinct MRGPRX2 antagonists were identified with one, Compound B, being orally active and demonstrating high potency in blocking Substance P-mediated degranulation using freshly isolated human skin mast cells with half maximal inhibitory concentration (IC 50 ) at 0.42 nM. Compound B also potently blocked Substance P-stimulated histamine release from resident mast cells in a human skin explant setup as well as blocking itch in an established behavioral scratching model using MRGPRX2 knock-in mice. Unlike human mast cells, Substance P failed to elicit a functional response in human basophils., Conclusion: These data fully support the investigation of MRGPRX2 receptor antagonists in mast cell-driven allergic skin disorders such as chronic spontaneous urticaria., Competing Interests: CHM, DVP, TR, DAG, SKP, and ZW are all employees of GSK. PSS is the Head of R&D at RefLab, and KB is an employee of RefLab. XD is the scientific co-founder and a consultant of Escient Pharmaceuticals and collaborator with GSK on MRGPRX projects. The remaining author declares 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 © 2024 Macphee, Dong, Peng, Paone, Skov, Baumann, Roethke, Goldspink, Pearson and Wu.)

Previous time-integrated (2 h to 4 h) measurements show that total gas-phase water-soluble organic carbon (WSOC g ) is 10 to 20 times higher inside homes compared to outside. However, concentration dynamics of WSOC g and total particle phase WSOC (WSOC p )-are not well understood. During the Chemical Assessment of Surfaces and Air (CASA) experiment, we measured concentration dynamics of WSOC g and WSOC p inside a residential test facility in the house background and during scripted activities. A total organic carbon (TOC) analyzer pulled alternately from a particle-into-liquid sampler (PILS) or a mist chamber (MC). WSOC g concentrations (215 ± 29 μg-C m -3 ) were generally 36× higher than WSOC p (6 ± 3 μg-C m -3 ) and 20× higher than outdoor levels. A building-specific emission factor ( E f ) of 31 mg-C h -1 maintained the relatively high house WSOC g background, which was dominated by ethanol (46 μg-C m -3 to 82 μg-C m -3 ). When we opened the windows, WSOC g decayed slower (2.8 h -1 ) than the air change rate (21.2 h -1 ) and E f increased (243 mg-C h -1 ). The response (increased E f ) suggests WSOC g concentrations are regulated by large near surface reservoirs rather than diffusion through surface materials. Cooking and ozone addition had a small impact on WSOC, whereas surface cleaning, volatile organic compound (VOC) additions, or wood smoke injections had significant impacts on WSOC concentrations. WSOC g concentration decay rates from these activities (0.4 h -1 to 4.0 h -1 ) were greater than the normal operating 0.24 h -1 air change rate, which is consistent with an important role for surface removal.

Per- and polyfluoroalkyl substances (PFAS) are prevalent in consumer products used indoors. However, few measurements of ionic PFAS exist for indoor air. We analyzed samples collected on PM 2.5 quartz fiber filters (QFFs) in 11 North Carolina homes 1-3 times in living rooms (two QFFs in series), and immediately outside each home (single QFF), for 26 ionic PFAS as part of the 9 months Indoor PFAS Assessment (IPA) Campaign. All targeted PFAS, except for PFDS and 8:2 monoPAP, were detected indoors. PFBA, PFHpA, PFHxA, PFOA, PFOS, and 6:2 diPAP were detected in >50% of indoor samples. PFHxA, PFOA, and PFOS had the highest detection frequency (DF = 80%; medians = 0.5-0.7 pg m -3 ), while median PFBA concentrations (3.6 pg m -3 ; DF = 67%) were highest indoors. Residential indoor air concentrations (sum of measured PFAS) were, on average, 3.4 times higher than residential outdoor air concentrations, and an order of magnitude higher than regional background concentrations. Indoor-to-outdoor emission rate estimates suggest that emissions from single unit homes could be a meaningful contributor to PFBA, PFOA, and PFOS emissions in populated areas far from major point sources. Backup QFFs were observed to adsorb some targeted PFAS from the gas-phase, making reported values upper-bounds for particle-phase and lower-bounds for total air (gas plus particle) concentrations. We found that higher concentrations of carbonaceous aerosol were associated with a shift in partitioning of short chain PFCAs and long chain PFSAs toward the particle phase.

Introduction: Cervical cancer disproportionally affects Black and Latinx women in Chicago. Black and Latinx women have a higher incidence of cervical cancer diagnosis and lower rates of cervical cancer screening than non-Latinx White women. Self-collected high-risk human papillomavirus (HPV) testing has been proposed as a method to address these barriers to screening and prevent cervical cancer., Objective: This study aimed to understand the feasibility and acceptability of self-collected HPV testing as a novel approach to address barriers to cervical cancer screening for Black and Latinx women in Chicago., Methods: Semistructured interviews with 17 Black and Latinx community members of the greater Chicago area were conducted. Thematic analysis using inductive and deductive coding was completed., Results: Findings from qualitative interviews indicate strong support for self-collected HPV testing among community members. They expressed a preference for self-collected HPV testing due to the comfort, control, and reduced anxiety it offers. Financial constraints, prioritization of other life demands, and past trauma were identified as substantial barriers to traditional cervical screening., Conclusion: Self-collected HPV testing could address barriers to cervical cancer screening by providing a less-invasive, patient-centered alternative to traditional methods. Self-collected HPV testing should be made accessible, be integrated into existing cervical cancer screening programs, and be covered by health insurance., (© The Author(s) 2024. Published by Mary Ann Liebert, Inc.)

Particle therapy (PT) represents a significant advancement in cancer treatment, precisely targeting tumor cells while sparing surrounding healthy tissues thanks to the unique depth-dose profiles of the charged particles. Furthermore, their linear energy transfer and relative biological effectiveness enhance their capability to treat radioresistant tumors, including hypoxic ones. Over the years, extensive research has paved the way for PT's clinical application, and current efforts aim to refine its efficacy and precision, minimizing the toxicities. In this regard, radiobiology research is evolving toward integrating biotechnology to advance drug discovery and radiation therapy optimization. This shift from basic radiobiology to understanding the molecular mechanisms of PT aims to expand the therapeutic window through innovative dose delivery regimens and combined therapy approaches. This review, written by over 30 contributors from various countries, provides a comprehensive look at key research areas and new developments in PT radiobiology, emphasizing the innovations and techniques transforming the field, ranging from the radiobiology of new irradiation modalities to multimodal radiation therapy and modeling efforts. We highlight both advancements and knowledge gaps, with the aim of improving the understanding and application of PT in oncology., 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 Authors.)

The growing interest in chemoinformatic model uncertainty calls for a summary of the most widely used regression techniques and how to estimate their reliability. Regression models learn a mapping from the space of explanatory variables to the space of continuous output values. Among other limitations, the predictive performance of the model is restricted by the training data used for model fitting. Identification of unusual objects by outlier detection methods can improve model performance. Additionally, proper model evaluation necessitates defining the limitations of the model, often called the applicability domain. Comparable to certain classifiers, some regression techniques come with built-in methods or augmentations to quantify their (un)certainty, while others rely on generic procedures. The theoretical background of their working principles and how to deduce specific and general definitions for their domain of applicability shall be explained., (© 2024 The Authors. Molecular Informatics published by Wiley-VCH GmbH.)

A cross-sectional survey among religious brothers and sisters (n = 250) with their specific lifestyle and related spiritual practices stated moments of awe perceptions. They responded to both the Awe/Gratitude scale and to free text fields to substantiate their quantitative responses. Qualitative content analysis of their free text responses resulted in six main categories of awe triggers: (1) Nature, (2) Special Moments, (3) Transcendence Perceptions, (4) Religious practices, (5) Distinct People, and (6) Aesthetics, Art and Culture. Awe perceptions can be an immediate feeling and the outcome of a process of reflection in response to admiration, inspiration, and elevation. As these perceptions are related to psychological well-being and prosocial behaviors, their training can generate positive effects on quality of life., (© 2024. The Author(s).)

Importance: Lesbian, gay, and bisexual populations face barriers accessing health care in Chicago, Illinois., Objective: To describe the prevalence of up-to-date cervical cancer screening among lesbian, gay, and bisexual vs heterosexual cisgender women in Chicago., Design, Setting, and Participants: This retrospective, cross-sectional, population-based study of cisgender women residing in Chicago was completed from 2020 to 2022 using data from the Healthy Chicago Survey, which is conducted annually by the Chicago Department of Public Health. Participants included cisgender women aged 25 to 64 years with no history of hysterectomy. Respondents who self-identified as lesbian, gay, or bisexual or other than straight, lesbian, or bisexual were coded as lesbian, gay, or bisexual (LGB). Respondents who self-identified as straight were coded as heterosexual. Those who reported having a Papanicolaou test within the past 3 years were considered up-to-date with cervical cancer screening. Data analysis was performed from June to October 2023., Exposures: The primary exposure was sexual orientation. Covariates included age, income level, race, ethnicity, having a primary care practitioner (PCP), and insurance coverage., Main Outcomes and Measures: Prevalence ratios (PRs), log-based regression models, and interaction analysis were used to describe the association of sexual orientation with up-to-date screening., Results: The sample included 5167 cisgender women (447 LGB and 4720 heterosexual), aged 25 to 64 years, with no history of hysterectomy. Among LGB cisgender women, 318 (71.14%) reported previous cervical cancer screening compared with 3632 (76.95%) heterosexual cisgender women. The prevalence of up-to-date screening was 10% lower in the LGB group compared with the heterosexual group (PR, 0.90; 95% CI, 0.82-1.00). In regression analysis, having a PCP (PR, 1.43; 95% CI, 1.29-1.59) was associated with up-to-date screening. In interaction analysis, LGB cisgender women with a PCP were 93% more likely to be up-to-date compared with those without a PCP (PR, 1.93; 95% CI, 1.37-2.72)., Conclusions and Relevance: In this cross-sectional study of cervical cancer screening rates between the heterosexual and LGB populations in Chicago, up-to-date cervical cancer screening was associated with having a PCP, regardless of sexual orientation, but this association was greater for LGB individuals. Although LGB populations were less likely to be screened, this disparity may be reduced with more consistent health care access and established care with PCPs.

Background & Aims: CD4 T cells shape the neutralizing antibody (nAb) response and facilitate viral clearance in various infections. Knowledge of their phenotype, specificity and dynamics in hepatitis E virus (HEV) infection is limited. HEV is enterically transmitted as a naked virus (nHEV) but acquires a host-derived quasi-envelope (eHEV) when budding from cells. While nHEV is composed of the open reading frame (ORF)-2-derived capsid, eHEV particles also contain ORF3-derived proteins. We aimed to longitudinally characterize the HEV-specific CD4 T cells targeting ORF1, 2 and 3 and antibodies against nHEV or eHEV in immunocompetent individuals with acute and resolved HEV infection., Methods: HEV-specific CD4 T cells were analyzed by intracellular cytokine staining after stimulation with in silico-predicted ORF1- and ORF2-derived epitopes and overlapping peptides spanning the ORF3 region. Ex vivo multiparametric characterization of capsid-specific CD4 T cells was performed using customized MHC class II tetramers. Total and neutralizing antibodies targeting nHEV or eHEV particles were determined., Results: HEV-specific CD4 T-cell frequencies and antibody titers are highest in individuals with acute infection and decline in a time-dependent process with an antigen hierarchy. HEV-specific CD4 T cells strongly target the ORF2-derived capsid and ORF3-specific CD4 T cells are hardly detectable. NAbs targeting nHEV are found in high titers while eHEV particles are less efficiently neutralized. Capsid-specific CD4 T cells undergo memory formation and stepwise contraction, accompanied by dynamic phenotypical and transcriptional changes over time., Conclusion: The viral capsid is the main target of HEV-specific CD4 T cells and antibodies in acute-resolving infection, correlating with efficient neutralization of nHEV. Capsid-specific immunity rapidly emerges followed by a stepwise contraction several years after infection., Impact and Implications: The interplay of CD4 T cells and neutralizing antibody responses is critical in the host defense against viral infections, yet little is known about their characteristics in hepatitis E virus (HEV) infection. We conducted a longitudinal study of immunocompetent individuals with acute and resolved HEV infection to understand the characteristics of HEV-specific CD4 T cells and neutralizing antibodies targeting different viral proteins and particles. We found that HEV-specific CD4 T cells mainly target capsid-derived epitopes. This correlates with efficient neutralization of naked virions while quasi-enveloped particles are less susceptible to neutralization. As individuals with pre-existing liver disease and immunocompromised individuals are at risk for fulminant or chronic courses of HEV infection, these individuals might benefit from the development of vaccination strategies which require a detailed knowledge of the composition and longevity of HEV-specific CD4 T-cell and antibody immunity., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10 -8 ). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC., (© 2024. The Author(s).)

Over the decades our understanding of lichens has shifted to the fact that they are multiorganismic, symbiotic microecosystems, with their complex interactions coming to the fore due to recent advances in microbiomics. Here, we present a mutualistic-parasitic continuum dynamics scenario between an orange lichen and a lichenicolous fungus from the Atacama Desert leading to the decay of the lichen's photobiont and leaving behind a black lichen thallus. Based on isolation, sequencing, and ecophysiological approaches including metabolic screenings of the symbionts, we depict consequences upon infection with the lichenicolous fungus. This spans from a loss of the lichen's photosynthetic activity and an increased roughness of its surface to an inhibition of the parietin synthesis as a shared pathway between the photobiont and the mycobiont, including a shift of secondary metabolism products. This degree of relations has rarely been documented before, although lichenicolous fungi have been studied for over 200 years, adding an additional level to the view of interactions within lichens.

Alzheimer's Disease (AD) is the most widespread form of dementia, with one of the pathological hallmarks being the formation of neurofibrillary tangles (NFTs). These tangles consist of phosphorylated Tau fragments. Asparagine endopeptidase (AEP) is a key Tau cleaving enzyme that generates aggregation-prone Tau fragments. Inhibition of AEP to reduce the level of toxic Tau fragment formation could represent a promising therapeutic strategy. Here, we report the first orthosteric, selective, orally bioavailable, and brain penetrant inhibitors with an irreversible binding mode. We outline the development of the series starting from reversible molecules and demonstrate the link between inhibition of AEP and reduction of Tau N368 fragment both in vitro and in vivo .

Pharmacological challenge models are deployed to evaluate drug effects during clinical development. Intradermal injection of Substance P (SP) neuropeptide, a potential challenge agent for investigating local mediators, is associated with wheal and flare response mediated by the MRGPRX2 receptor. Although dose-dependent data on SP effects exist, full characterization and information on potential carryover effect after repeated challenge are lacking. This open-label, two-part, prospective enabling study of SP intradermal challenge in healthy participants aimed to understand and distinguish between wheal and flare responses following various SP doses. Part 1 included one challenge visit to determine optimum SP dose range for evaluation in part 2, which determined variability in 20 participants and used intradermal microdialysis (IDM) for SP-challenged skin sampling. At 5, 15, 50, and 150 pmol doses, respectively, posterior median area under the curve (AUC; AUC 0-2h ) was 4090.4, 5881.2, 8846.8, and 9212.8 mm 2 /min, for wheal response, and 12020.9, 38154.3, 65470.6, and 67404.4 mm 2 /min for flare response (SP-challenge visit 2). When the challenge was repeated ~2 weeks later, no carryover effect was observed. IDM histamine levels were relatively low, resulting in low confidence in the data to define temporal characteristics for histamine release following SP challenge. No safety concerns were identified using SP. Wheal and flare responses following intradermal SP challenge were dose-dependent and different. The results indicate that this challenge model is fit-for-purpose in future first-in-human studies and further assessment of novel drugs targeting dermal inflammatory disease responses, such as chronic spontaneous urticaria, chronic inducible urticaria, and pseudo-allergic reactions., (© 2023 GlaxoSmithKline. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: More than 25 years after the end of the Balkan war, many people belonging to the post-war population are still traumatized by the war events and have been treated for post-traumatic stress disorder or other psychiatric diagnoses. We were interested in their Inner Peace needs, how these relate to indicators of mental health, and their needs to clarify open processes in their lives and to forgive and be forgiven., Materials and Methods: In a cross-sectional survey with standardized questionnaires (i.e., SpNQ, PCL-M, HADS, and BMLSS), 638 male patients who were treated in seven psychiatric centers in Croatia were enrolled. 68% were diagnosed with PTSD and 32% had other psychiatric diagnoses. Most had actively participated in the Balkan war (79%), and 60% for the whole war period., Results: Strong needs to "immerse into beauty of nature" were stated by 47%, to "dwell at a place of quietness and peace" by 66%, and to "find inner peace" by 57%. These Inner Peace needs were highest in men treated with PTSD diagnoses as compared to men with other psychiatric diagnoses and were slightly lower in men who were active during the whole war period as compared to shorter phases of war participation. Regression analyses with Inner Peace needs as a dependent variable revealed that Clarification/Forgiveness needs were the best predictor, with further influences of PTSD symptoms and life satisfaction, explaining altogether 49% of the variance. The best predictors of their PTSD symptoms were life satisfaction, perceived burden, depressive symptoms, Inner Peace needs, religious trust, and duration of war participation, explaining 60% of the variance., Conclusion: In Croatian male war participants in clinical treatment decades after the war, Inner Peace needs indicate their ongoing intention to let go of their disturbing experiences and to find states of inner peace, particularly at specific places of quietness and peace. These needs can be considered metaphors for longing for wholeness, integrity, and safety, in contrast to the ongoing impact of unresolved issues. Thus, apart from psychotherapeutic treatment, sheltered places of nature, inspiration, and reconciliation might be elements to improve the difficult situation of post-war victims still suffering from their experiences., Competing Interests: The authors 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 Glavas, Büssing and Baumann.)