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Paleontologists have long stressed the need to know how sampling the fossil record might influence our knowledge of the evolution of life. Here, we combine fossil occurrences of North American marine invertebrates from the Paleobiology Database with lithologic data from Macrostrat to identify sampling patterns in carbonate and siliciclastic rocks. We aim to quantify temporal trends in sampling effort within and between lithologies, focusing on the proportion of total available volume that has been sampled (sampled fossiliferous proportion, here called κ). Results indicate that the sampled fossiliferous proportion was stable during the Paleozoic, and variable during the post-Paleozoic, but showed no systematic increase through time. Fossiliferous carbonate rocks are proportionally more sampled than siliciclastic rocks, with intervals where the carbonate κ is double the siliciclastic κ. Among possible explanations for the apparent oversampling of fossiliferous carbonate rocks, analyses suggest that barren units, taphonomic dissolution, or data entry errors cannot completely explain sampling patterns. Our results suggest that one of the important drivers might be that paleontologists publish taxonomic descriptions from carbonate rocks more frequently. The higher diversity in carbonate rocks might account for an ease in the description of unknown species and therefore a higher rate of published fossils. Finally, a strong effect in favor of carbonate rocks might distort our perception of diversity through time, even under commonly used standardization methods. Our results also confirm that previous descriptions of an increase in the proportion of sampled fossiliferous rocks over time were driven by the sampling of the nonmarine fossil record.

Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding the molecular recognition of RNA structures by small molecules. Here we studied molecular recognition patterns between a natural-product-inspired small-molecule collection and three-dimensionally folded RNA structures. Mapping these interaction landscapes across the human transcriptome defined structure–activity relationships. Although RNA-binding compounds that bind to functional sites were expected to elicit a biological response, most identified interactions were predicted to be biologically inert as they bind elsewhere. We reasoned that, for such cases, an alternative strategy to modulate RNA biology is to cleave the target through a ribonuclease-targeting chimera, where an RNA-binding molecule is appended to a heterocycle that binds to and locally activates RNase L1. Overlay of the substrate specificity for RNase L with the binding landscape of small molecules revealed many favourable candidate binders that might be bioactive when converted into degraders. We provide a proof of concept, designing selective degraders for the precursor to the disease-associated microRNA-155 (pre-miR-155), JUN mRNA and MYC mRNA. Thus, small-molecule RNA-targeted degradation can be leveraged to convert strong, yet inactive, binding interactions into potent and specific modulators of RNA function.

The purpose of this study was to examine the relationship between place image and attitudes toward cities with the moderating effect of sporting event awareness. Exploratory research was conducted using a mall-intercept sampling technique with a sample of 299 local residents. PLS-SEM using SmartPLS 3.3.2 was performed to test the hypothesized relationships. The findings demonstrated a significant relationship between place image and resident attitudes. In addition, a reflective–formative construct of place image showed that municipal facilities, leisure, and public services were significant factors in influencing perceptions of place image. The moderating effect of awareness was not found to be significant. The results of this study recommend that city authorities and tourism managers recognize and address the various dimensions of place image to increase community support. This would benefit event managers through developing favorable attitudes of residents towards their cities, thus having a social impact on the host city's residents.

Child psychiatry access programs (CPAPs) provide primary care providers (PCPs) with assistance in mental health diagnosis, management, and resource navigation.Data collected from DC Mental Health Access in Pediatrics (MAP) included PCPs and patient demographics, clinical encounter information, and provider satisfaction.DC MAP consult volume increased 349.3% over the first 5 years. Services requested included care coordination (85.8%), psychiatric consultation (21.4%), and psychology/social work consultation (9.9%). Of psychiatry-involved consultations, PCPs managed patient medication care with DC MAP support 50.5% of the time. Most (94.1%) PCPs said they would recommend colleagues use DC MAP, and 29.6% reported diverting patients from the emergency departments using DC MAP.DC MAP grew quickly, highlighting program impact and need. Demand for care coordination required flexible staffing and highlighted the need for coordination in pediatrics. Child psychiatry access programs offer an innovative way to enhance PCP management of their patients' mental health needs.

Operando soft and hard X-ray spectroscopic techniques were used in combination with plane-wave density functional theory (DFT) simulations to rationalize the enhanced activities of Zn-containing Cu nanostructured electrocatalysts in the electrocatalytic CO2 hydrogenation reaction. We show that at a potential for CO2 hydrogenation, Zn is alloyed with Cu in the bulk of the nanoparticles with no metallic Zn segregated; at the interface, low reducible Cu(I)-O species are consumed. Additional spectroscopic features are observed, which are identified as various surface Cu(I) ligated species; these respond to the potential, revealing characteristic interfacial dynamics. Similar behavior was observed for the Fe-Cu system in its active state, confirming the general validity of this mechanism; however, the performance of this system deteriorates after successive applied cathodic potentials, as the hydrogen evolution reaction then becomes the main reaction pathway. In contrast to an active system, Cu(I)-O is now consumed at cathodic potentials and not reversibly reformed when the voltage is allowed to equilibrate at the open-circuit voltage; rather, only the oxidation to Cu(II) is observed. We show that the Cu-Zn system represents the optimal active ensembles with stabilized Cu(I)-O; DFT simulations rationalize this observation by indicating that Cu-Zn-O neighboring atoms are able to activate CO2, whereas Cu-Cu sites provide the supply of H atoms for the hydrogenation reaction. Our results demonstrate an electronic effect exerted by the heterometal, which depends on its intimate distribution within the Cu phase and confirms the general validity of these mechanistic insights for future electrocatalyst design strategies.

Understanding the generation of mechanical stress in drying, particle-laden films is important for a wide range of industrial processes. One way to study these stresses is through the cantilever experiment, whereby a thin film is deposited onto the surface of a thin plate that is clamped at one end to a wall. The stresses that are generated in the film during drying are transmitted to the plate and drive bending. Mathematical modelling enables the film stress to be inferred from measurements of the plate deflection. The aim of this paper is to present simplified models of the cantilever experiment that have been derived from the time-dependent equations of continuum mechanics using asymptotic methods. The film is described using nonlinear poroelasticity and the plate using nonlinear elasticity. In contrast to Stoney-like formulae, the simplified models account for films with non-uniform thickness and stress. The film model reduces to a single differential equation that can be solved independently of the plate equations. The plate model reduces to an extended form of the Föppl-von Kármán (FvK) equations that accounts for gradients in the longitudinal traction acting on the plate surface. Consistent boundary conditions for the FvK equations are derived by resolving the Saint-Venant boundary layers at the free edges of the plate. The asymptotically reduced models are in excellent agreement with finite element solutions of the full governing equations. As the Péclet number increases, the time evolution of the plate deflection changes from $t$ to $t^{1/2}$ , in agreement with experiments.

During tumor evolution, cancer cells can acquire the ability to proliferate, invade neighboring tissues, evade the immune system, and spread systemically. Tracking this process remains challenging, as many key events occur stochastically and over long times, which could be addressed by studying the phylogenetic relationships among cancer cells. Several lineage tracing approaches have been developed and employed in many tumor models and contexts, providing critical insights into tumor evolution. Recent advances in single-cell lineage tracing have greatly expanded the resolution, scale, and readout of lineage tracing toolkits. In this review, we provide an overview of static lineage tracing methods, and then focus on evolving lineage tracing technologies that enable reconstruction of tumor phylogenies at unprecedented resolution. We also discuss in vivo applications of these technologies to profile subclonal dynamics, quantify tumor plasticity, and track metastasis. Finally, we highlight outstanding questions and emerging technologies for building comprehensive cancer evolution roadmaps.

Samples from avian species of high conservation concern are often low in total genomic DNA (gDNA). Feathers are collected more frequently than blood, yet they contain low total gDNA which can present challenges in using them for genomics. Whole Genome Sequencing (WGS) can provide many insights that can be used to aid in species conservation, but current methods for working with feathers are cost prohibitive for population level genomic analyses. Thus, there is a need for a cost-effective method of preparing WGS libraries from feathers. To bridge the gap between sampling techniques commonly used in avian conservation genetics that yield low total gDNA and the powerful tool of WGS, we developed a method that successfully produces WGS libraries from feather gDNA with as low input as 0.48 ng of DNA and an average final library size of 300–500 base pairs. Sequencing results suggest high sequencing quality using our protocol with feather DNA. We conclude that our method will facilitate high-throughput WGS on low total gDNA samples, like feathers, thus expanding the power of genomic tools in critical avian conservation research.

The utility of teacher evaluation depends on meaningful teacher engagement with evaluation processes. However, critics of traditional tenure policies suggest that tenure nullifies teacher engagement with practices to improve performance. This study investigates whether tenured teachers exhibit perceptions that reflect disengagement with evaluation and feedback and whether perceptions of evaluation vary based on teachers having received tenure under a reformed system that restricts lifetime protections conditional on continual high evaluation scores. Using statewide administrative and survey data from Tennessee, the study employs propensity score methods to isolate differences in perceptions between comparable groups of tenured and untenured teachers. Results show that tenured teachers report more negative perceptions of evaluation in their district; however, this difference is concentrated among those who received permanent tenure status prior to the reformed tenure system. The study concludes by discussing implications and directions for future research.

Astrocytes are integral components of brain circuits, where they sense, process, and respond to surrounding activity, maintaining homeostasis and regulating synaptic transmission, the sum of which results in behavior modulation. These interactions are possible due to their complex morphology, composed of a tree-like structure of processes to cover defined territories ramifying in a mesh-like system of fine leaflets unresolved by conventional optic microscopy. While recent reports devoted more attention to leaflets and their dynamic interactions with synapses, our knowledge about the tree-like 'backbone' structure in physiological conditions is incomplete. Recent transcriptomic studies described astrocyte molecular diversity, suggesting structural heterogeneity in regions such as the hippocampus, which is crucial for cognitive and emotional behaviors. In this study, we carried out the structural analysis of astrocytes across the hippocampal subfields of Cornu Ammonis area 1 (CA1) and dentate gyrus in the dorsoventral axis. We found that astrocytes display heterogeneity across the hippocampal subfields, which is conserved along the dorsoventral axis. We further found that astrocytes appear to contribute in an exocytosis-dependent manner to a signaling loop that maintains the backbone structure. These findings reveal astrocyte heterogeneity in the hippocampus, which appears to follow layer-specific cues and depend on the neuro-glial environment.

Transcriptional enhanced associate domain (TEAD) proteins together with their transcriptional coactivator yes-associated protein (YAP) and transcriptional coactivator with the PDZ-binding motif (TAZ) are important transcription factors and cofactors that regulate gene expression in the Hippo pathway. In mammals, the TEAD families have four homologues: TEAD1 (TEF-1), TEAD2 (TEF-4), TEAD3 (TEF-5), and TEAD4 (TEF-3). Aberrant expression and hyperactivation of TEAD/YAP signaling have been implicated in a variety of malignancies. Recently, TEADs were recognized as being palmitoylated in cells, and the lipophilic palmitate pocket has been successfully targeted by both covalent and noncovalent ligands. In this report, we present the medicinal chemistry effort to develop MYF-03–176 (compound 22) as a selective, cysteine-covalent TEAD inhibitor. MYF-03–176 (compound 22) significantly inhibits TEAD-regulated gene expression and proliferation of the cell lines with TEAD dependence including those derived from mesothelioma and liposarcoma.

Metabolic networks are interconnected and influence diverse cellular processes. The protein-metabolite interactions that mediate these networks are frequently low affinity and challenging to systematically discover. We developed mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS) to identify such interactions. Analysis of 33 enzymes from human carbohydrate metabolism identified 830 protein-metabolite interactions, including known regulators, substrates, and products as well as previously unreported interactions. We functionally validated a subset of interactions, including the isoform-specific inhibition of lactate dehydrogenase by long-chain acyl–coenzyme A. Cell treatment with fatty acids caused a loss of pyruvate-lactate interconversion dependent on lactate dehydrogenase isoform expression. These protein-metabolite interactions may contribute to the dynamic, tissue-specific metabolic flexibility that enables growth and survival in an ever-changing nutrient environment.

Self-injurious thoughts and behaviors (SITB) increase dramatically across adolescence. Despite the prevalence and severity of these outcomes, remarkably little research has elucidated why adolescence represents a particularly high-risk period for the emergence of SITB. Recent theoretical models have posited that SITB may result from failures in biological stress regulation in the context of social stress. However, there is a lack of data examining these associations during the transition to adolescence, a sensitive period of development that is characterized by changes across socio-affective and psychophysiological domains that may interact to heighten risk for SITB. The present study used a prospective longitudinal design among 147 adolescents. We built on advantages offered by the RDoC framework to test the interaction of experiences of social conflict (i.e., parent and peer conflict) with cardiac arousal (i.e., resting heart rate) to predict adolescent non-suicidal self-injury (NSSI) and suicidal ideation (SI) across one year. Longitudinal analyses revealed that while neither greater peer conflict nor higher cardiac arousal at baseline were associated with SITB outcomes at follow-up, adolescents experiencing the combination of greater peer conflict and higher cardiac arousal at baseline showed significant longitudinal increases in NSSI at follow-up. In addition, there were null effects for family conflict and SI outcomes. Findings indicate that youth with greater peer conflict and heightened arousal during the transition to adolescence may be at increased risk for NSSI. Future research should examine these processes at finer timescales in order to elucidate whether these factors are proximal predictors of within-day SITB.

From its first colonisation in the early 1600s, Bermuda was known as a potentially profitable whaling site. Humpback whales (Megaptera novaeangliae) were common in coastal waters during the late winter and spring (March-May); sperm whales (Physeter macrocephalus), in offshore waters probably throughout much of the year. Initial efforts at shore whaling in 1616-17 were not very successful but whaling continued at least intermittently until 1685 when Bermuda became a Crown Colony and the whaling industry was placed on a firm footing. The shore whaling industry in Bermuda was never particularly large or profitable. Although it continued into the 20th century and was episodically re-invigorated with new financing and equipment, shore whaling never met the high expectations of those who invested in it. In the 1780s and for several decades thereafter, a few whaling voyages sailed from Bermuda for distant whaling grounds in the South Atlantic and Indo-Pacific, targeting sperm whales and right whales (Eubalaena spp.). There is no evidence to suggest that local catches by Bermudian shore whalers exceeded more than a few tens of whales per year, the vast majority of them humpback whales.

58 p.-5 fig.-7 box., Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease., I. Vitale is and has been supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC, IG 2017 #20417 and IG 2022 #27685) and by a startup grant from the Italian Institute for Genomic Medicine (Candiolo, Turin, Italy) and Compagnia di San Paolo (Torino, Italy). M. Piacentini, G. Melino, S. Melino, G. Ciliberto are supported by the Ministro dell’Università (Italy) progetto Heal Italia PE6. L. Galluzzi is/has been supported (as a PI unless otherwise indicated) by two Breakthrough Level 2 grants from the US DoD BCRP (#BC180476P1; #BC210945), by a Transformative Breast Cancer Consortium Grant from the US DoD BCRP (#W81XWH2120034, PI: Formenti), by a U54 grant from NIH/NCI (#CA274291, PI: Deasy, Formenti, Weichselbaum), by the 2019 Laura Ziskin Prize in Translational Research (#ZP-6177, PI: Formenti) from the Stand Up to Cancer (SU2C), by a Mantle Cell Lymphoma Research Initiative (MCL-RI, PI: Chen-Kiang) grant from the Leukemia and Lymphoma Society (LLS), by a Rapid Response Grant from the Functional Genomics Initiative (New York, US), by startup funds from the Dept. of Radiation Oncology at Weill Cornell Medicine (New York, US), by industrial collaborations with Lytix Biopharma (Oslo, Norway), Promontory (New York, US) and Onxeo (Paris, France), as well as by donations from Promontory (New York, US), the Luke Heller TECPR2 Foundation (Boston, US), Sotio a.s. (Prague, Czech Republic), Lytix Biopharma (Oslo, Norway), Onxeo (Paris, France), Ricerchiamo (Brescia, Italy), and Noxopharm (Chatswood, Australia). G. Kroemer is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; European Research Council Advanced Investigator Grand “ICD-Cancer”, Fondation pour la Recherche Médicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases (EJPRD); European Research Council (ICD-Cancer), European Union Horizon 2020 Projects Oncobiome and Crimson; Fondation Carrefour; Institut National du Cancer (INCa); Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); a Cancer Research ASPIRE Award from the Mark Foundation; the RHU Immunolife; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM)

ObjectiveTo examine time from screening to diagnostic workup, biopsy, and surgery for non-Hispanic White (NHW) and Black women following implementation of a same-day biopsy program.MethodsAll NHW and Black women with BI-RADS category 0 screening mammogram at Duke University Hospital were identified between August 1, 2020, and August 1, 2021. Patient characteristics were recorded. Time between screening mammogram, diagnostic workup, breast biopsy, surgical consultation, and surgery were recorded. Comparisons were made between NHW and Black women using a multivariable regression model. Diagnostic imaging to biopsy time interval was compared to historical averages before same-day biopsy implementation.ResultsThere were 2156 women: 69.9% NHW (1508/2156) and 30.1% Black (648/2156). Mean ± standard deviation time from screening to diagnostic imaging overall was 13.5 ± 32.5 days but longer for Black (18.0 ± 48.3 days) than for NHW women (11.5 ± 22.2 days) (P ConclusionDisparities exist along the breast imaging pathway. A same-day biopsy program benefited NHW women more than Black women.

Health care spending in Italy is high and continues to increase; assessing the long-term health and economic outcomes of new therapies is essential. Atopic dermatitis (AD) is a chronic, pruritic, immune-mediated inflammatory dermatosis, a clinical condition that significantly affects patients’ quality of life at a high cost and requires continuous care. This retrospective study aimed to assess the direct cost and adverse drug reactions (ADRs) of Dupilumab and patients’ clinical outcomes. All AD patients treated with Dupilumab at the Sassari University Hospital, Italy, between January 2019 and December 2021 were included. Eczema Area Severity Index, Dermatology Life Quality Index, and Itch Numeric Rating Scale scores were measured. ADRs and drug expenses were analyzed. A statistically significant posttreatment improvement was observed for all the indices measured: EASI ( P < 0.0001 ), DLQI ( P < 0.0001 ), NRS ( P < 0.0001 ). The total expenditure for Dupilumab, in the observed period, amounted to € 589.748,66 for 1358 doses, and a positive correlation was shown between annual expenditure and delta percentage of variation pre- and posttreatment for the clinical parameters evaluated.