DeepGSEA: explainable deep gene set enrichment analysis for single-cell transcriptomic data.

MOTIVATION: Gene set enrichment (GSE) analysis allows for an interpretation of gene expression through pre-defined gene set databases and is a critical step in understanding different phenotypes. With the rapid development of single-cell RNA sequencing (scRNA-seq) technology, GSE analysis can be performed on fine-grained gene expression data to gain a nuanced understanding of phenotypes of interest. However, with the cellular heterogeneity in single-cell gene profiles, current statistical GSE analysis methods sometimes fail to identify enriched gene sets. Meanwhile, deep learning has gained traction in applications like clustering and trajectory inference in single-cell studies due to its prowess in capturing complex data patterns. However, its use in GSE analysis remains limited, due to interpretability challenges. RESULTS: In this paper, we present DeepGSEA, an explainable deep gene set enrichment analysis approach which leverages the expressiveness of interpretable, prototype-based neural networks to provide an in-depth analysis of GSE. DeepGSEA learns the ability to capture GSE information through our designed classification tasks, and significance tests can be performed on each gene set, enabling the identification of enriched sets. The underlying distribution of a gene set learned by DeepGSEA can be explicitly visualized using the encoded cell and cellular prototype embeddings. We demonstrate the performance of DeepGSEA over commonly used GSE analysis methods by examining their sensitivity and specificity with four simulation studies. In addition, we test our model on three real scRNA-seq datasets and illustrate the interpretability of DeepGSEA by showing how its results can be explained. AVAILABILITY AND IMPLEMENTATION: https://github.com/Teddy-XiongGZ/DeepGSEA.

Human red blood cells express the RNA sensor TLR7.

Red blood cells (RBCs) express the nucleic acid-binding toll-like receptor 9 (TLR9) and bind CpG-containing DNA. However, whether human RBCs express other nucleic acid-binding TLRs is unknown. Here we show that human RBCs express the RNA sensor TLR7. TLR7 is present on the red cell membrane and is associated with the RBC membrane protein Band 3. In patients with SARS-CoV2-associated sepsis, TLR7-Band 3 interactions in the RBC membrane are increased when compared with healthy controls. In vitro, RBCs bind synthetic ssRNA and RNA from ssRNA viruses. Thus, RBCs may serve as a previously unrecognized sink for exogenous RNA, expanding the repertoire of non-gas exchanging functions performed by RBCs.

Randomized Feasibility Study Evaluating Multiple FDA-approved Microbubbles for CEUS Lymphography.

Prior studies on contrast-enhanced ultrasound (CEUS) lymphography for preoperative mapping before lymphaticovenous anastomosis surgery in patients with extremity lymphedema have been limited to using only Lumason and Sonazoid as microbubble contrast agents. The purpose of this study was to determine the feasibility of using two other Food & Drug Administration-approved microbubble agents, Optison and Definity, for imaging lymphatic vessels in the upper extremities. Nine female adults with unilateral upper extremity lymphedema anticipating lymphaticovenous anastomosis surgery underwent CEUS lymphography of the unaffected upper extremity randomized to either Lumason, Definity, or Optison. Lymphatic vessels were visualized in all but one case when undilated Definity was used. In the eight upper extremities where lymphatic vessels were visualized, an average of eight intradermal injections of microbubbles were performed in the extremity. Lymphatic vessels could be identified in 57% (36 of 63) of the injections. The effective dilution for each of the microbubble agents is provided. This was the first successful demonstration of lymphatic vessel visualization using either Definity or Optison. Broadening the range of available microbubble agents for CEUS lymphography could improve accessibility to the procedure and provide potentially safer alternatives.

Minority Stress, Psychological Distress, Sexual Compulsivity, and Avoidance-Based Motivations Associated with Methamphetamine Use Among Sexual Minority Men Living with HIV: Examining Direct and Indirect Associations Using Cross-Sectional Structural Equation Modeling.

OBJECTIVE: Sexual minority men (SMM) living with HIV report significantly greater methamphetamine use compared with heterosexual and HIV-negative peers. Greater use may be related to stressors (e.g., HIV-related stigma) faced by SMM living with HIV and subsequent psychological and behavioral sequelae. We tested an integrated theoretical model comprised of pathways between stigma, discrimination, childhood sexual abuse, psychological distress, sexual compulsivity, and cognitive escape in predicting methamphetamine use among SMM living with HIV. METHODS: Among 423 SMM living with HIV, we tested a structural equation model examining factors hypothesized to be directly and indirectly associated with methamphetamine use. Analyses were adjusted for demographic covariates and sampling bias. RESULTS: The model showed good fit (CFI = 0.96, RMSEA = 0.01). Heterosexist discrimination was associated with psychological distress (ß = 0.39, p < 0.001) and psychological distress was associated with sexual compulsivity (ß = 0.33, p < 0.001). Sexual compulsivity was associated with cognitive escape (ß = 0.31, p < 0.001), which was associated with methamphetamine use (ß = 0.51, p < 0.001). Psychological distress was associated with methamphetamine use via serial indirect effects of sexual compulsivity and cognitive escape (ß = 0.05, p < 0.05). CONCLUSIONS: Heterosexist discrimination contributed to psychological distress among SMM living with HIV. Psychological distress is linked to methamphetamine use via sexual compulsivity and cognitive avoidance. Interventions seeking to reduce the likelihood that SMM living with HIV use methamphetamine should include coping strategies specific to heterosexism and related psychological distress.

Quantifying the regime of thermodynamic control for solid-state reactions during ternary metal oxide synthesis.

The success of solid-state synthesis often hinges on the first intermediate phase that forms, which determines the remaining driving force to produce the desired target material. Recent work suggests that when reaction energies are large, thermodynamics primarily dictates the initial product formed, regardless of reactant stoichiometry. Here, we validate this principle and quantify its constraints by performing in situ characterization on 37 pairs of reactants. These experiments reveal a threshold for thermodynamic control in solid-state reactions, whereby initial product formation can be predicted when its driving force exceeds that of all other competing phases by ≥60 milli-electron volt per atom. In contrast, when multiple phases have a comparable driving force to form, the initial product is more often determined by kinetic factors. Analysis of the Materials Project data shows that 15% of possible reactions fall within the regime of thermodynamic control, highlighting the opportunity to predict synthesis pathways from first principles.

Refocusing the microbial rare biosphere concept through a functional lens.

The influential concept of the rare biosphere in microbial ecology has underscored the importance of taxa occurring at low abundances yet potentially playing key roles in communities and ecosystems. Here, we refocus the concept of rare biosphere through a functional trait-based lens and provide a framework to characterize microbial functional rarity, a combination of numerical scarcity across space or time and trait distinctiveness. We demonstrate how this novel interpretation of the rare biosphere, rooted in microbial functions, can enhance our mechanistic understanding of microbial community structure. It also sheds light on functionally distinct microbes, directing conservation efforts towards taxa harboring rare yet ecologically crucial functions.

Assessing numeracy and medication calculations within undergraduate nursing education: A qualitative study.

AIM: To explore how undergraduate nursing students are assessed on nursing numeracy and medication calculations from the perspective of Australian nurse education leaders. DESIGN: A qualitative study. METHODS: Semi-structured interviews were conducted with 17 nurse education leaders between November 2022 and January 2023. Braun and Clarke's six phases of thematic analysis were used to analyse the data. RESULTS: Five key themes were identified: (i) high expectations to keep the public safe, (ii) diverse assessment formats, (iii) different ways of managing assessment integrity, (iv) assessment conditions incongruent to the clinical setting and (v) supporting struggling students. CONCLUSION: Nurse education leaders set high standards requiring students to achieve 100% in numeracy and medication calculation assessments, thus maintaining the reputation of nursing and patient safety. However, students struggled to meet this expectation. Diverse assessment formats were implemented, with some examination conditions contrary to clinical practice. Currently, there is no benchmark or independent point of registration examination in Australia, hence the problem is each university had a different standard to judge students' competence. Gaining insight into how these assessments are conducted provides an opportunity to work towards an evidence-based model or benchmark for the assessment of numeracy. IMPLICATIONS FOR THE PROFESSION: Dosage errors in clinical practice threaten patient safety and the reputation of the nursing profession. The accuracy rate of calculations by undergraduate and registered nurses is deficient worldwide. This research highlights a major educational issue, that being the wide variation in how numeracy assessments are conducted with no clear pedagogical rationale for a standardised method. Such assessments would establish a national standard, contributing to quality assurance, the development of the nursing profession and improve patient safety.

Sodium-enriched nectar shapes plant-pollinator interactions in a subalpine meadow.

Many plants have evolved nutrient rewards to attract pollinators to flowers, but most research has focused on the sugar content of floral nectar resources. Concentrations of sodium in floral nectar (a micronutrient in low concentrations in nectar) can vary substantially both among and within co-occurring species. It is hypothesized that sodium concentrations in floral nectar might play an important and underappreciated role in plant-pollinator interactions, especially because many animals, including pollinators, are sodium limited in nature. Yet, the consequences of variation in sodium concentrations in floral nectar remain largely unexplored. Here, we investigate whether enriching floral nectar with sodium influences the composition, diversity, and frequency of plant-pollinator interactions. We experimentally enriched sodium concentrations in four plant species in a subalpine meadow in Colorado, USA. We found that flowers with sodium-enriched nectar received more visits from a greater diversity of pollinators throughout the season. Different pollinator species foraged more frequently on flowers enriched with sodium and showed evidence of other changes to foraging behavior, including greater dietary evenness. These findings are consistent with the "salty nectar hypothesis," providing evidence for the importance of sodium limitation in pollinators and suggesting that even small nectar constituents can shape plant-pollinator interactions.

Direct Lithium Extraction from α-Spodumene through Solid-State Reactions for Sustainable Li2CO3 Production.

With increasing battery demand comes a need for diversified Li sources beyond brines. Among all Li-bearing minerals, spodumene is most often used for its high Li content and natural abundance. However, the traditional approach to process spodumene is costly and energy-intensive, requiring the mineral be transformed from its natural α to ß phase at >1000 °C. Acid leaching is then applied, followed by neutralization to precipitate Li2CO3. In this work, we report an alternative method to extract Li directly from α-spodumene, which is performed at lower temperatures and avoids the use of acids. It is shown that Li2CO3 is formed with >90% yield at 750 °C by reacting α-spodumene with Na2CO3 and Al2O3. The addition of Al2O3 is critical to reduce the amount of Li2SiO3 that forms when only Na2CO3 is used, instead providing increased thermodynamic driving force to form NaAlSiO4 and Li2CO3 as the sole products. We find that this reaction is most effective at 4 h, after which volatility limits the yield. Following its extraction, Li2CO3 can be isolated by washing the sample using deionized water. This energy-saving and acid-free route to obtain Li2CO3 directly from spodumene can help meet the growing demand for Li.

Effect of personality traits, psychological resilience and life adversities on lifetime violence trajectories: A novel classification model in schizophrenia.

The risk of violence is higher in schizophrenia spectrum disorders (SSD) compared to the general population and it is a pressing and understudied issue. Several dispositional and environmental factors have been previously correlated with violence, however, there has been little success in assessing their ability to predict violence patterns across the life span. This study aims to assess violence prediction based on personality traits, psychological resilience, and life-course adversities in a non-forensic population of SSD patients. In a sample of 231 patients with SSD, we assessed violence using the Brown-Goodwin History of Lifetime Aggression Scale and conducted cross-sectional assessments of possible predictors such as childhood trauma, personality traits and resilience scores. We then utilized a logistic regression classification algorithm to predict different violence trajectories based on the proposed risk factors. Our model significantly predicted individuals with violence in both childhood and adulthood, as well as childhood-only violence (p < 0.001). However, the model did not show significance for adult-only violence (p = 0.604). In all given trajectories, female sex appeared to be protective against violence, while stressful life events appeared to contribute to it. These results suggest that distinct factors can better inform risk assessment of lifespan violence patterns for personalized interventions in SSD.

Fast clustering and cell-type annotation of scATAC data using pre-trained embeddings.

Data from the single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) are now widely available. One major computational challenge is dealing with high dimensionality and inherent sparsity, which is typically addressed by producing lower dimensional representations of single cells for downstream clustering tasks. Current approaches produce such individual cell embeddings directly through a one-step learning process. Here, we propose an alternative approach by building embedding models pre-trained on reference data. We argue that this provides a more flexible analysis workflow that also has computational performance advantages through transfer learning. We implemented our approach in scEmbed, an unsupervised machine-learning framework that learns low-dimensional embeddings of genomic regulatory regions to represent and analyze scATAC-seq data. scEmbed performs well in terms of clustering ability and has the key advantage of learning patterns of region co-occurrence that can be transferred to other, unseen datasets. Moreover, models pre-trained on reference data can be exploited to build fast and accurate cell-type annotation systems without the need for other data modalities. scEmbed is implemented in Python and it is available to download from GitHub. We also make our pre-trained models available on huggingface for public use. scEmbed is open source and available at https://github.com/databio/geniml. Pre-trained models from this work can be obtained on huggingface: https://huggingface.co/databio.

Halogenated Phenylpyridines Possessing Chemo-Selectivity for Diverse Molecular Architectures.

Pentafluoropyridine was used as a molecular building block for the installation of aryl bromides, affording a series of multisubstituted halogenated arenes. This operationally simplistic methodology offers precise regioselectivity, ease of scalability, and high purity. 19F Nuclear magnetic resonance (NMR) served as a key diagnostic tool for structural characterization, given the sensitivity with various aryl bromine substitutions on the fluorinated pyridine ring. Furthermore, molecular modeling simulations offered insight into this new class of halogenated phenylpyridines and their unique electronic and reactive properties. This study also demonstrates examples of efficient chemo-selectivity upon either metal-catalyzed aryl-aryl coupling or nucleophilic aromatic substitution of the aryl bromide or fluorinated pyridine scaffold, respectively. A diverse pool of polyarylene structures with high degree of complexity, functionalized linear polymers, and controlled network architectures were achieved from this simple methodology.

Nurse academics' self-reported insights into the teaching of undergraduate nursing numeracy: A national cross-sectional study.

AIMS: The aim of this research was to explore the teaching of undergraduate nursing numeracy in tertiary education settings in Australia. Specifically, it explored and identified: (1) the most common basic numeracy concepts taught, (2) additional training and resources to support numeracy teaching, (3) who is best placed to teach numeracy and (4) the preferred methods of teaching medication calculations. BACKGROUND: Nurse academics are required to teach nursing numeracy to undergraduate nursing students who enter university unprepared to accurately calculate medication dosages. It is important that students understand numeracy concepts as this is then applied to contextualised clinical applications. Nurse academics teach basic numeracy; however, the literature reveals that nurse academics do not consider themselves mathematics teachers and that experts in this area are better suited to teaching this skill. There are a dearth of studies about the nurse academics who conduct the teaching and this study seeks to fill that gap by exploring firsthand the nurse academics' self-reported insights into the teaching of undergraduate nursing numeracy. DESIGN: Cross-sectional survey. The setting was Australian universities that deliver an accredited undergraduate nursing degree. METHODS: Purposive sampling was used to recruit Australian nurse academics (n = 170), sessional or permanent who currently teach all aspects of nursing numeracy and medication calculations to undergraduate nursing students. Data were collected between Nov 2023 - Feb 2024 using an online survey platform and analysed using a descriptive content analysis. RESULTS: Nurse academics taught basic arithmetic most commonly (92 %), yet most (90 %) had not received professional development or additional training in how to teach these concepts. To assist with numeracy teaching, resources were requested (47 %) as were the need for mathematics learning support staff (82 %). The formula method was most commonly taught (91 %), however, most participants (94 %) were willing to learn and to teach other methods of calculating medications. CONCLUSIONS: This research suggests an evidenced-based education framework be created to support and guide nurse academics when teaching all aspects of nursing numeracy and medication calculations. Building the teaching capacity of nurse academics in this vital area will enhance student competence and contribute to patient safety.

Effects of the toxic dinoflagellate, Alexandrium pacificum, on the marine diatom, Chaetoceros muelleri, and mussel (Perna canaliculus) sperm and hemocytes.

Harmful algal blooms (HABs) of Alexandrium pacificum have affected the Marlborough Sounds in New Zealand since 2010, posing a threat to green-lipped mussel (GLM, Perna canaliculus) farming. Previous studies have shown A. pacificum has negative effects GLM embryos and larvae. To further investigate these toxic mechanisms, in vitro bioassays were conducted on GLM spermatozoa, hemocytes, and the diatom, Chaetoceros muelleri. The three cell types were exposed to several treatments of A. pacificum for 2 h and responses were measured using flow cytometry and pulse amplitude-modulated fluorometry. Significant spermatozoa mortality was recorded in treatments containing A. pacificum cells or fragments, while hemocyte and C. muelleri mortality was recorded in cell-free treatments of A. pacificum which contained paralytic shellfish toxins (PSTs). Variation in sensitivity between cell types as well as the sublethal effects observed, emphasise the diverse toxic mechanisms of A. pacificum on co-occurring species in the environment.

Implicit bias and experience influence overall but not relative trustworthiness judgment of other-race faces.

Impressions of trustworthiness are formed quickly from faces. To what extent are these impressions shared among observers of the same or different races? Although high consensus of trustworthiness evaluation has been consistently reported, recent studies suggested substantial individual differences. For instance, negative implicit racial bias and low contact experience towards individuals of the other race have been shown to be related to low trustworthiness judgments for other-race faces. This pre-registered study further examined the effects of implicit social bias and experience on trustworthiness judgments of other-race faces. A relatively large sample of White (N = 338) and Black (N = 299) participants completed three tasks: a trustworthiness rating task of faces, a race implicit association test, and a questionnaire of experience. Each participant rated trustworthiness of 100 White faces and 100 Black faces. We found that the overall trustworthiness ratings for other-race faces were influenced by both implicit bias and experience with individuals of the other-race. Nonetheless, when comparing to the own-race baseline ratings, high correlations were observed for the relative differences in trustworthiness ratings of other-race faces for participants with varied levels of implicit bias and experience. These results suggest differential impact of social concepts (e.g., implicit bias, experience) vs. instinct (e.g., decision of approach-vs-avoid) on trustworthiness impressions, as revealed by overall vs. relative ratings on other-race faces.

Self-Assembled Tetranuclear Square Complex of Chromium(III) Bridged by Radical Pyrazine: A Molecular Model for Metal-Organic Magnets.

The attractive electronic properties of metal-pyrazine materials─electrical conductivity, magnetic order, and strong magnetic coupling─can be tuned in a wide range depending on the metal employed, as well as its ligand-imposed redox environment. Using solvent-directed synthesis to control the dimensionality of such systems, a discrete tetranuclear chromium(III) complex, exhibiting a rare example of bridging radical pyrazine, has been prepared from chromium(II) triflate and neutral pyrazine. The strong antiferromagnetic interaction between CrIII (S = 3/2) and radical pyrazine (S = 1/2) spins, theoretically estimated at about -932 K, leads to a thermally isolated ST = 4 ground state, which remains the only populated state observable even at room temperature.

Observation of stacking engineered magnetic phase transitions within moiré supercells of twisted van der Waals magnets.

Recent demonstrations of moiré magnetism, featuring exotic phases with noncollinear spin order in the twisted van der Waals (vdW) magnet chromium triiodide CrI3, have highlighted the potential of twist engineering of magnetic (vdW) materials. However, the local magnetic interactions, spin dynamics, and magnetic phase transitions within and across individual moiré supercells remain elusive. Taking advantage of a scanning single-spin magnetometry platform, here we report observation of two distinct magnetic phase transitions with separate critical temperatures within a moiré supercell of small-angle twisted double trilayer CrI3. By measuring temperature-dependent spin fluctuations at the coexisting ferromagnetic and antiferromagnetic regions in twisted CrI3, we explicitly show that the Curie temperature of the ferromagnetic state is higher than the Néel temperature of the antiferromagnetic one by ~10 K. Our mean-field calculations attribute such a spatial and thermodynamic phase separation to the stacking order modulated interlayer exchange coupling at the twisted interface of moiré superlattices.

Children and young adults with newly diagnosed rhabdomyosarcoma metastatic to bone treated on Children's Oncology Group studies.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Despite bone metastases being present in 5% of patients at diagnosis, there are limited studies examining these outcomes. We sought to define the prognostic factors, clinical courses, and outcomes of children treated on Children's Oncology Group (COG) clinical trials with RMS metastatic to bone at diagnosis. METHODS: We performed a retrospective analysis of patients diagnosed with bone metastatic RMS enrolled on COG RMS clinical trials (D9802, D9803, ARST0431, or ARST08P1) between 1997 and 2013. RESULTS: RMS metastatic to bone was identified in 154 patients at a median age of 14.9 years at diagnosis. Fifty-eight percent of patients were male, 90% had metastases at additional sites, 74% had alveolar histology, and extremity was the most common primary site (31%). Eighty-six percent of patients (n = 133) received radiation therapy. The 3- and 5-year event-free survival (EFS) was 15.4% and 14.5%, respectively. The 3- and 5-year overall survival (OS) was 30.4% and 18.0%, respectively. We identified alveolar histology, FOXO1 fusion presence, unfavorable primary location, higher Oberlin score, and lack of radiation as poor prognostic characteristics for both EFS and OS in univariate analysis. Lack of radiation was not significant when excluding patients with events prior to 20 weeks. CONCLUSIONS: This study is the largest analysis of patients with bone metastatic RMS, and defines the poor overall outcomes and negative prognostic factors for these patients. They may be eligible for therapy deintensification for improved quality of life or pursuit of novel treatments/approaches, which are desperately needed.

A Systematic Review of Family History, Race/Ethnicity, and Genetic Risk on Prostate Cancer Detection and Outcomes: Considerations in PSA-based Screening.

AIM: To investigate the role of family history, race/ethnicity, and genetics in prostate cancer (PCa) screening. METHODS: We conducted a systematic review of articles from January 2013 through September 2023 that focused on the association of race/ethnicity and genetic factors on PCa detection. Of 10,815 studies, we identified 43 that fulfilled our pre-determined PICO (Patient, Intervention, Comparison and Outcome) criteria. RESULTS: Men with ≥1 first-degree relative(s) with PCa are at increased risk of PCa, even with negative imaging and/or benign prostate biopsy. Black men have higher PCa risk, while Asian men have lower risk. Most of the differences in risks are attributable to environmental and socioeconomic factors; however, genetic differences may play a role. Among numerous pathogenic variants that increase PCa risk, BRCA2, MSH2, and HOXB13 mutations confer the highest risk of PCa. Polygenic risk score (PRS) models identify men at higher PCa risk for a given age and PSA; these models improve when considering other clinical factors and when the model population matches the study population's ancestry. CONCLUSIONS: Family history of PCa, race/ethnicity, pathogenic variants (particularly BRCA2, MSH2, and HOXB13), and PRS are associated with increased PCa risk and should be considered in shared decision-making to determine PCa screening regimens.

PEPhub: a database, web interface, and API for editing, sharing, and validating biological sample metadata.

BACKGROUND: As biological data increase, we need additional infrastructure to share them and promote interoperability. While major effort has been put into sharing data, relatively less emphasis is placed on sharing metadata. Yet, sharing metadata is also important and in some ways has a wider scope than sharing data themselves. RESULTS: Here, we present PEPhub, an approach to improve sharing and interoperability of biological metadata. PEPhub provides an API, natural-language search, and user-friendly web-based sharing and editing of sample metadata tables. We used PEPhub to process more than 100,000 published biological research projects and index them with fast semantic natural-language search. PEPhub thus provides a fast and user-friendly way to finding existing biological research data or to share new data. AVAILABILITY: https://pephub.databio.org.