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Abstract Secondary activation of the endothelin system is thought to be involved in toxic liver injury. This study tested the hypothesis that dual endothelin-converting enzyme / neutral endopeptidase blockade might be able to attenuate acute toxic liver injury. Male Sprague-Dawley rats were implanted with subcutaneous minipumps to deliver the novel compound SLV338 (10 mg/kg*d) or vehicle. Four days later they received two intraperitoneal injections of D-galactosamine (1.3 g/kg each) or vehicle at an interval of 12 hours. The animals were sacrificed 48 hours after the first injection. Injection of D-galactosamine resulted in very severe liver injury, reflected by strongly elevated plasma liver enzymes, hepatic necrosis and inflammation, and a mortality rate of 42.9 %. SLV338 treatment did not show any significant effect on the extent of acute liver injury as judged from plasma parameters, hepatic histology and mortality. Plasma measurements of SLV338 confirmed adequate drug delivery. Plasma concentrations of big endothelin-1 and endothelin-1 were significantly elevated in animals with liver injury (5-fold and 62-fold, respectively). Plasma endothelin-1 was significantly correlated with several markers of liver injury. SLV338 completely prevented the rise of plasma big endothelin-1 (p < 0.05) and markedly attenuated the rise of endothelin-1 (p = 0.055). In conclusion, dual endothelin-converting enzyme / neutral endopeptidase blockade by SLV338 did not significantly attenuate D-galactosamine-induced acute liver injury, although it largely prevented the activation of the endothelin system. An evaluation of SLV338 in a less severe model of liver injury would be of interest, since very severe intoxication might not be relevantly amenable to pharmacological interventions.

Abstract Shortly after discovery of ET-1 in 1988, the entire endothelin system was characterized. The endothelin system consists of the three peptides ET-1, ET-2 and ET-3, their G-protein-coupled receptors endothelin receptor A and B (ETRA and ETRB) and the two endothelin-converting enzymes (ECE-1 and ECE-2). Genetically modified animal models are an important tool in biomedical research. Here we describe the key findings obtained from genetically modified animal models either over-expressing compounds of the ET system or lacking these compounds (knockout mice). Results from the different transgenic and knockout models disclose that the ET system plays a major role in embryonic development. Two ET system-dependent neural crest-driven developmental pathways become obvious: one of them being an ET-1/ETAR axis, responsible for cardio-renal function and development as well as cranial development; the other seems to be an ET-3/ETBR mediated signalling pathway. Mutations within this axis are associated with disruptions in epidermal melanocytes and enteric neurons. These findings led to the discovery of similar findings in humans with Hirschsprung disease. In adult life the ET system is most important in the cardiovascular system and plays a role in fibrotic remodelling of the heart, lung and kidney as well as in the regulation of water and salt excretion.

While annotated treebanks are an invaluable tool in linguistic research, the tree-based form in which corpus search tools often present search results is not necessarily well-suited to the user’s requirements. We argue that a concordance style export of search results, built around a user-identified "key node" in the query, represents a useful synoptic view of the data for the user needing to carry out further manual analysis of query results. We present a first implementation of these 'KNIC' concordances for an Old French corpus, using the TigerSearch treebank search engine integrated into the TXM corpus analysis platform.

More than 2 million older Americans from underrepresented racial and ethnic minority groups (URGs) have early-stage Alzheimer's disease and related dementias (ADRD). There are very few scalable recruitment strategies, particularly for Black older adults, to accelerate participation in ADRD research. The Indiana Alzheimer's Disease Research Center (IADRC) and its Community Advisory Board developed and implemented the innovative RAAISE-D Framework. This Framework informed the creation of community-first recruitment strategies designed to accelerate participation of Black older adults in ADRD research. Preliminary outcomes from its implementation included the doubling of Black adult enrollment (46, 13.4% to 101, 26.9%) from April 2020 to April 2024. Black adults were more likely to have normal cognition, be female, and ≤ 12 years of education than non-Hispanic White adults. The RAAISE-D Framework identified key concepts for URG focused recruitment strategies which successfully accelerated enrollment of Black adults in ADRD research and could be generalized to other URGs. HIGHLIGHTS: RAAISE-D Framework provides adaptable URG recruitment strategies. IADRC CAB-researcher partnership was the foundation of community-first methodology. RAAISE-D Framework doubled the Black enrollment in the IADRC in 4 years., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The present study was based on empirical data collected during the first phase (2016) of Study 1000, part of the 13-November Program: a corpus of 934 individual interviews conducted 6-11 months after the events. To process this empirical material, the authors used integrated TXM software, which provides several classic textometry tools. They mainly used the lexical specificity analysis tool, which statistically measures the irregularity of the word distribution according to the parts of the corpus. They also analyzed the concordances of certain very specific lexical forms. Analysis revealed the important influence of social roles on the construction of memories and narratives of this event. Application of textometry tools highlighted lexical fields specific to the different social roles played by the interviewees in this social drama , and showed that it was through these specific vocabularies that they remembered and recounted this extraordinary story. Social roles therefore influence the formation of memories both individual and collective, by modulating the way in which individuals select what to remember and what to forget. The article opens up several interesting avenues for future analyses, mainly a longitudinal perspective (including phases 2 and 3 of Study 1000) for the study of flashbulb memories and the gender issue to fine-tune the analysis of social roles., 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 © 2024 Orianne, Heiden, Klein-Peschanski, Eustache and Peschanski.)

Background: Maternal symptoms of anxiety and depression are highly prevalent during pregnancy and postpartum and have the potential to impact fetal development and offspring behavior. However, research on the effects of fetal exposure to maternal subclinical affective symptoms on infant self-regulation is still lacking. Self-regulation provides a fundamental precondition for healthy development and overall life success whereas dysfunctional self-regulation can lead to behavioral problems, poor academic achievement, social rejection, and physical/mental disorders. During pregnancy and infancy, children largely depend upon their mothers in order to successfully regulate their internal states. Given the high prevalence of mothers suffering from anxiety and depressive symptoms during pregnancy and after childbirth, the aim of the present study is to explore how maternal affective symptoms change during the pre- and postnatal period, and how measures obtained in pregnancy and beyond impact self-regulation in infants, as indicated by crying-, sleeping-, and/or feeding problems., Methods: This prospective longitudinal study investigates the effects of maternal symptoms of depression, anxiety, and pregnancy-specific anxiety on infant's self-regulation in N = 225 mother-infant dyads. Maternal affective symptoms were examined at five prenatal and three postnatal time-points using the Edinburgh Postnatal Depression Scale (EPDS), the State-Trait Anxiety Inventory (STAI) and the Pregnancy Related Anxiety Questionnaire Revised (PRAQ-R2). Infant's self-regulation was assessed twice - at the age of three and six months - using the Crying Feeding Sleeping Scale (SFS)., Results: Maternal pregnancy-specific anxiety was the most significant predictor for infant self-regulatory problems. It predicted crying-, sleeping, and feeding problems and explained up to 18 % of the variance. Even when controlling for maternal postpartum affective symptoms, pregnancy-specific anxiety remained a significant predictor for infant self-regulation problems., Limitations: Rather homogenous sample (high socioeconomic status). Data based on maternal reports of infant behavior., Conclusions: Our results suggest that fetal exposure to maternal affective symptoms - specifically pregnancy-related anxiety - plays a substantial role in the development of infant self-regulation problems, potentially mediated by epigenetic modifications. Importantly, even though maternal symptoms of depression and anxiety only reached subclinical levels, they were predictive for infant crying-, sleeping-, and feeding problems. Our findings underline the importance of early prevention and clearly tailored interventions during pregnancy and postpartum to prevent adverse outcome for mother, child and family., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier B.V.)

The literatures on affordance perception and psychophysics are seminal in the basic study of perception and action. Nevertheless, the application of classic psychophysical methodologies/analysis to the study of affordance perception remains unexplored. In four experiments, we investigated the Stevens' power law scaling of affordance perception. Participants reported maximum forward reaching ability with a series of rods (both seated and standing) for themselves and another person (confederate). Participants also reported a property of the rod set that has been explored in previous psychophysical experiments and changes in equal measure with forward reach-with-ability (length). In all, we found that affordance perception reports (β = .32) were an underaccelerated function of actual changes in reaching ability compared with relatively less accelerated length reports (β = .73). Affordance perception scaled with stimulus magnitude more similarly to brightness perception than length perception. Furthermore, affordance perception reports scaled similarly regardless of the actor (self and other), task context (seated and standing), or idiosyncrasies of the measurement procedure (controlling for distance compression effects), while length perception reports were sensitive to location/distance compression effects. We offer empirical and theoretical considerations, along with pathways for future research., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: The study examined Black and White prospective participants' views of barriers to and facilitators of participation in Alzheimer's disease (AD) biomarker research., Methods: In a mixed-methods study, 399 community-dwelling Black and White older adults (age ≥55) who had never participated in AD research completed a survey about their perceptions of AD biomarker research. Individuals from lower socioeconomic and education backgrounds and Black men were over-sampled to address perspectives of traditionally under-represented groups. A subset of participants ( n = 29) completed qualitative interviews., Results: Most participants expressed interest in biomarker research (overall 69%). However, Black participants were comparatively more hesitant than White participants (28.9% vs 15.1%), were more concerned about study risks (28.9% vs 15.1%), and perceived multiple barriers to participating in brain scans. These results persisted even after adjusting for trust and perceived knowledge of AD. Information was a primary barrier (when absent) and incentive (when provided) for AD biomarker research participation. Black older adults desired more information about AD (eg, risk, prevention), general research processes, and specific biomarker procedures. They also desired return of results to make informed decisions about their health, research-sponsored community awareness events, and for researchers to mitigate the burden placed on participants in research (eg, transportation, basic needs)., Conclusion: Our findings increase representativeness in the literature by focusing on individuals with no history of AD research experience and those from traditionally underrepresented groups in research. Results suggest that the research community needs to improve information sharing and raising awareness, increase their presence in the communities of underrepresented groups, reduce incidental costs, and provide valuable personal health information to participants to increase interest. Specific recommendations for improving recruitment are addressed. Future studies will assess the implementation of evidence-based, socioculturally sensitive recruitment strategies to increase enrollment of Black older adults into AD biomarker studies. HIGHLIGHTS: Individuals from under-represented groups are interested in Alzheimer's disease (AD) biomarker research.After adjusting for trust and AD knowledge, Black participants were still more hesitant.Information is a barrier (when absent) to and incentive (when given) for biomarker studies.Reducing burden (e.g., transportation) is essential for recruiting Black older adults., Competing Interests: None of the investigators have a conflict of interest. JE receives support from Veterans Affairs (VA) IK2 HX002283, National Institute on Aging (NIA; P30 AG10133, P30 AG072976), Veterans Health Affairs, Health Services Research and Development Career Development Award [16‐153], and Academy of Communication in Health Putnam Scholar Fellowship. AJP receives support from NIA (U01 AG057195, P30AG072976, P30AG010133) and Alzheimer's Association (LDRFP‐21‐818464). SG receives report from the NIA (P30AG072976, P30AG010133). SLR receives support from the NIA (K01AG049060; R01 AG061788; P30 AG010133, P30 AG072976; New Vision Award) and Eli Lilly, Biogen, and Eisai. AJS receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U01 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, and U01 AG068057 and U01 AG072177). He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of Positron Emission Tomography [PET] tracer precursor); Bayer Oncology (Scientific Advisory Board); Eisai (Scientific Advisory Board); Siemens Medical Solutions USA, Inc. (Dementia Advisory Board); Springer‐Nature Publishing (Editorial Office Support as Editor‐in‐Chief, Brain Imaging and Behavior). SW receives support from the NIA (K23AG062555, P30AG072976, P30AG010133, R21AG074179) and the VA for clinical services. She receives book royalties from American Psychiatry Publishing Institute and consultant fees from Data Safety Monitoring Board., (© 2023 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Community advisory boards (CABs) and researcher partnerships present a promising opportunity to accelerate enrollment of underrepresented groups (URGs). We outline the framework for how the CAB and researchers at the Indiana Alzheimer's Disease Research Center (IADRC) partnered to accelerate URG participation in AD neuroimaging research., Methods: CAB and the IADRC researchers partnered to increase the CAB's impact on URG study enrollment through community and research interactions. Community interactions included the CAB collaboratively building a network of URG focused community organizations and collaborating with those URG-focused organizations to host IADRC outreach and recruitment events. Research interactions included direct impact (CAB members referring themselves or close contacts as participants) and strategic impact, mainly by the CAB working with researchers to develop and refine URG focused outreach and recruitment strategies for IADRC and affiliated studies to increase URG representation. We created a database infrastructure to measure how these interactions impacted URG study enrollment., Results: Out of the 354 URG research referrals made to the IADRC between October 2019 and December 2022, 267 referrals were directly referred by the CAB ( N = 36) or from community events in which CAB members organized and/or volunteered at ( N = 231). Out of these 267 referrals, 34 were enrolled in IADRC and 2 were enrolled in Indiana University Longitudinal Early Onset AD Study (IU LEADS). Of note, both studies require the prospective participants to be willing to do MRI and PET scans. As of December 2022, 30 out of the 34 enrolled participants have received a consensus diagnosis; the majority were cognitively normal (64.7%), with the remainder having mild cognitive impairment (17.6%) or early-stage AD (2.9%)., Discussion: The IADRC CAB-researcher partnership had a measurable impact on the enrollment of African American/Black adults in AD neuroimaging studies. Future studies will need to test whether this conceptual model works for other sites and for other URGs., Competing Interests: No conflicts of interest are present for any of the authors. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The split-and-pool method has been widely used to synthesize chemical libraries of a large size for early drug discovery, albeit without the possibility of meaningful quality control. In contrast, a self-assembled DNA-encoded chemical library (DEL) allows us to construct an m x n-member library by mixing an m-member and an n-member pre-purified sub-library. Herein, we report a trio-pharmacophore DEL (T-DEL) of m x l x n members through assembling three pre-purified and validated sub-libraries. The middle sub-library is synthesized using DNA-templated synthesis with different reaction mechanisms and designed as a linkage connecting the fragments displayed on the flanking two sub-libraries. Despite assembling three fragments, the resulting compounds do not exceed the up-to-date standard of molecular weight regarding drug-likeness. We demonstrate the utility of T-DEL in linker optimization for known binding fragments against trypsin and carbonic anhydrase II and by de novo selections against matrix metalloprotease-2 and -9., (© 2023. The Author(s).)

Background: Since social distancing during the COVID-19-pandemic had a profound impact on professional life, this study investigated the effect of PCR testing on on-site work., Methods: PCR screening, antibody testing, and questionnaires offered to 4,890 working adults in Lower Saxony were accompanied by data collection on demographics, family status, comorbidities, social situation, health-related behavior, and the number of work-related contacts. Relative risks (RR) with 95 % confidence intervals were estimated for the associations between regular PCR testing and other work and health-related variables, respectively, and working on-site. Analyses were stratified by the suitability of work tasks for mobile office., Results: Between April 2020 and February 2021, 1,643 employees underwent PCR testing. Whether mobile working was possible strongly influenced the work behavior. Persons whose work was suitable for mobile office (mobile workers) had a lower probability of working on-site than persons whose work was not suitable for mobile office (RR = 0.09 (95 % CI: 0.07 - 0.12)). In mobile workers, regular PCR-testing was slightly associated with working on-site (RR = 1.19 (0.66; 2.14)). In those whose working place was unsuitable for mobile office, the corresponding RR was 0.94 (0.80; 1.09). Compared to persons without chronic diseases, chronically ill persons worked less often on-site if their workplace was suitable for mobile office (RR = 0.73 (0.40; 1.33)), but even more often if their workplace was not suitable for mobile office (RR = 1.17 (1.04; 1.33))., Conclusion: If work was suitable for mobile office, regular PCR-testing did not have a strong effect on presence at the work site., Trial Registration: An ethics vote of the responsible medical association (Lower Saxony, Germany) retrospectively approved the evaluation of the collected subject data in a pseudonymized form in the context of medical studies (No. Bo/30/2020; Bo/31/2020; Bo/32/2020)., (© 2023. The Author(s).)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has created a public crisis. Many medical and public institutions and businesses went into isolation in response to the pandemic. Because SARS-CoV-2 can spread irrespective of a patient's course of disease, these institutions' continued operation or reopening based on the assessment and control of virus spread can be supported by targeted population screening. For this purpose, virus testing in the form of polymerase chain reaction (PCR) analysis and antibody detection in blood can be central. Mobile SARS-CoV-2 screening facilities with a built-in biosafety level (BSL)-2 laboratory were set up to allow the testing offer to be brought close to the subject group's workplace. University staff members, their expertise, and already available equipment were used to implement and operate the screening facilities and a certified diagnostic laboratory. This operation also included specimen collection, transport, PCR and antibody analysis, and informing subjects as well as public health departments. Screening facilities were established at different locations such as educational institutions, nursing homes, and companies providing critical supply chains for health care. Less than 4 weeks after the first imposed lockdown in Germany, a first mobile testing station was established featuring a build-in laboratory with two similar stations commencing operation until June 2020. During the 15-month project period, approximately 33,000 PCR tests and close to 7000 antibody detection tests were collected and analyzed. The presented approach describes the required procedures that enabled the screening facilities and laboratories to collect and process several hundred specimens each day under difficult conditions. This report can assist others in establishing similar setups for pandemic scenarios., Competing Interests: The authors have declared no conflicts of interest., (© 2023 The Authors. Engineering in Life Sciences published by Wiley‐VCH GmbH.)

The Programme 13-Novembre aims to analyze the individual and collective memory of the terrorist attacks of November 13, 2015. At its heart is the Étude 1000, which is to gather the same 1000 people in audiovisual interviews four times in 10 years. Having the transcripts at our disposal, we choose here to show the importance of discourse analysis by recalling its theoretical foundations, to present one of the tools allowing this statistical analysis, the Correspondence Factor Analysis, and to use it to analyze the sub-corpus of interviews conducted at a distance from the Paris events, with 76 inhabitants of the Metz region. Crossing these volunteers with the words they use, we see that two variables clearly stand out that oppose the vocabularies, the gender variable and the age variable., (© Société de Biologie, 2023.)