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"Miller, Dan"
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Words that built a nation : voices of democracy that have shaped America's history
From the Constitution and the Gettysburg Address to the 2015 Supreme Court ruling on same-sex marriage, the updated collection preserves the documents of the first edition and introduces the landmark statements that are impacting our nation today.
Book
Lgr5+ telocytes are a signaling source at the intestinal villus tip
The intestinal epithelium is a structured organ composed of crypts harboring Lgr5+ stem cells, and villi harboring differentiated cells. Spatial transcriptomics have demonstrated profound zonation of epithelial gene expression along the villus axis, but the mechanisms shaping this spatial variability are unknown. Here, we combine laser capture micro-dissection and single cell RNA sequencing to uncover spatially zonated populations of mesenchymal cells along the crypt-villus axis. These include villus tip telocytes (VTTs) that express
Lgr5
, a gene previously considered a specific crypt epithelial stem cell marker. VTTs are elongated cells that line the villus tip epithelium and signal through Bmp morphogens and the non-canonical
Wnt5a
ligand. Their ablation is associated with perturbed zonation of enterocyte genes induced at the villus tip. Our study provides a spatially-resolved cell atlas of the small intestinal stroma and exposes
Lgr5
+ villus tip telocytes as regulators of the epithelial spatial expression programs along the villus axis.
Epithelial gene expression has been shown to be zonated along the crypt-villus axis, but mechanisms shaping this spatial variability were unknown. Here, Bahar Halpern et al. uncover zonation of mesenchymal cells, including Lgr5+ telocytes, which regulate epithelial gene expression at the villus tip.
Journal Article
Uniform genomic data analysis in the NCI Genomic Data Commons
The goal of the National Cancer Institute’s (NCI’s) Genomic Data Commons (GDC) is to provide the cancer research community with a data repository of uniformly processed genomic and associated clinical data that enables data sharing and collaborative analysis in the support of precision medicine. The initial GDC dataset include genomic, epigenomic, proteomic, clinical and other data from the NCI TCGA and TARGET programs. Data production for the GDC started in June, 2015 using an OpenStack-based private cloud. By June of 2016, the GDC had analyzed more than 50,000 raw sequencing data inputs, as well as multiple other data types. Using the latest human genome reference build GRCh38, the GDC generated a variety of data types from aligned reads to somatic mutations, gene expression, miRNA expression, DNA methylation status, and copy number variation. In this paper, we describe the pipelines and workflows used to process and harmonize the data in the GDC. The generated data, as well as the original input files from TCGA and TARGET, are available for download and exploratory analysis at the GDC Data Portal and Legacy Archive (
https://gdc.cancer.gov/
).
The Genomic Data Commons repository contains genomic, epigenomic, proteomic and clinical data from the TCGA and TARGET datasets. Here, the authors describe the analysis methods for how these divergent datasets were integrated together.
Journal Article
Auxotrophic interactions: a stabilizing attribute of aquatic microbial communities?
ABSTRACT
Auxotrophy, or an organism's requirement for an exogenous source of an organic molecule, is widespread throughout species and ecosystems. Auxotrophy can result in obligate interactions between organisms, influencing ecosystem structure and community composition. We explore how auxotrophy-induced interactions between aquatic microorganisms affect microbial community structure and stability. While some studies have documented auxotrophy in aquatic microorganisms, these studies are not widespread, and we therefore do not know the full extent of auxotrophic interactions in aquatic environments. Current theoretical and experimental work suggests that auxotrophy links microbial community members through a complex web of metabolic dependencies. We discuss the proposed ways in which auxotrophy may enhance or undermine the stability of aquatic microbial communities, highlighting areas where our limited understanding of these interactions prevents us from being able to predict the ecological implications of auxotrophy. Finally, we examine an example of auxotrophy in harmful algal blooms to place this often theoretical discussion in a field context where auxotrophy may have implications for the development and robustness of algal bloom communities. We seek to draw attention to the relationship between auxotrophy and community stability in an effort to encourage further field and theoretical work that explores the underlying principles of microbial interactions.
Discussion of the potential impact of auxotrophy, the requirement by an organism for an organic micronutrient, on the stability of aquatic microbial communities in the face of environmental changes.
Journal Article
Does Pornography Misinform Consumers? The Association between Pornography Use and Porn-Congruent Sexual Health Beliefs
Pornography may contribute to sexual health illiteracy due to its often fantastical and unrealistic depictions of sex. This cross-sectional study investigated whether pornography use was associated with holding porn-congruent sexual health beliefs among a sample of 276 Australian and Singaporean university students (Mage = 23.03, SDage = 7.06, 67.9% female, 47.8% Australian). The majority of participants (95.5% of males and 58.9% of females) reported viewing pornography in the past six months. Perceived realism of pornography and prior sexual experience were tested as potential moderators of the relationship between pornography use frequency and sexual health beliefs. Pornography use frequency showed no zero-order association with sexual health beliefs in the overall sample (although a significant zero-order association was observed among female participants). However, a significant positive association between porn use and porn-congruent sexual health beliefs was found in the overall sample, after controlling for demographic variables. Neither perceived realism nor sexual experience were found to act as moderators. Interestingly, prior sexual experience showed a significant zero-order association with sexual health beliefs, such that prior sexual experience was associated with holding porn-congruent beliefs. Perceived realism was unrelated to porn-congruent sexual health beliefs. The study provides some preliminary support for pornography having a misinformation effect on the sexual health knowledge of consumers.
Journal Article
Measuring Self-Perceived Effects of Pornography: A Short-Form Version of the Pornography Consumption Effects Scale
The Pornography Consumption Effects Scale (PCES) is a 47-item measure of self-perceived effects of pornography use. While the PCES is frequently used in the pornography research literature, its length may limit its applicability in some research situations. This study investigated if a short-form version of the PCES could be created for use with heterosexual men. The study employed an online sample of 312 self-identified heterosexual men. Confirmatory factor analysis was used to produce a 14-item version of the PCES. This short-form PCES (PCES-SF) showed excellent psychometric properties in terms of reliability, concurrent validity with the long-form PCES, and discriminant validity with respect to social desirability. Similar to the full-length PCES, the PCES-SF generates both an overall positive effect score and an overall negative effect score.
Journal Article
Can synthetic avatars replace lecturers? An exploratory international study of higher education stakeholder perceptions
Advances in technologies which use Generative Artificial Intelligence (GenAI) to mimic a person’s likeness or voice have led to growing interest in their use in educational contexts. However, little is known about how key stakeholders (teaching faculty and professional staff) perceive and intend to use these tools. This study investigates higher education employees’ perceptions and intentions regarding the use of synthetic avatars (alternatively known as deepfakes) through the lens of the Unified Theory of Acceptance and Use of Technology 2 (UTAUT2). Using a mixed-methods approach that combined quantitative survey data (
n
= 173) with qualitative text response, we found that academic stakeholders demonstrated a relatively low intention to adopt these technologies (
M
= 41.55,
SD
= 34.14) and held complex, often contradictory views about their implementation. Stakeholders identified potential benefits, including enhanced student engagement through interactions with historical figures, improved accessibility through voice synthesis, and reduced workload in content creation. However, they expressed significant concerns about the exploitation of academic labour, institutional cost-cutting leading to automation, degradation of human relationships in education, and broader societal impacts, such as environmental costs and information validity. Quantitative analysis revealed that adoption intentions were most strongly associated with hedonic motivation, with a gender-specific interaction in the evaluation of price value. Qualitative findings highlighted significant concerns regarding ethical implications, resource inequities, and the impact on professional identity. These results suggest that traditional technology acceptance models should be expanded to consider broader ethical and structural factors. Based on these findings, we propose a three-pillar framework for implementing synthetic avatar technologies in higher education that emphasises establishing robust institutional policies and governance structures, developing comprehensive professional development and support systems, and ensuring equitable resource allocation guided by evidence-based implementation strategies. This study enhances our understanding of how emerging AI technologies can be thoughtfully integrated into higher education while maintaining academic integrity and professional autonomy of educators.
Journal Article
Effective CAR T-cell targeting of an MUC1 cleavage product
BackgroundWe developed Chimeric antigen receptor (CAR) T cells targeting mucin 1 (MUC1)* (muk * (muk 1 star)), which is the tumor-associated growth factor receptor form of MUC1. Our antibody, MNC2, uniquely binds to MUC1* on cancer cells but does not bind to full-length MUC1, which is expressed on all normal epithelial cells. We tested the ability of the Tyr to Phe mutations in CD3ζ, known as “1XX”, to increase in vivo persistence and enable the recognition and killing of low antigen-expressing cancer cells.MethodsWe performed in vivo experiments comparing CARs with either 4-1BB or CD28 co-stimulatory domains, with or without the “1XX” Tyr to Phe mutations in ITAMs 2 and 3 of the CD3ζ signaling domain. All CARs were targeted to the tumor using the same huMNC2-scFv. To explore the sensitivity of each CAR, tumors comprising varying percentages of high MUC1* expressing cancer cells were xenografted. Further, wild-type low MUC1* expressing cells were engineered to fluoresce red while the cells engineered to express more MUC1* were made to fluoresce green. This experimental design allowed us to compare the sensitivity limits of the CARs against low versus high antigen-expressing cancer cells.ResultsAt high dose, all the CAR T cells effectively killed high antigen-expressing tumors in the short term. However, only the CAR bearing the 1XX mutations inhibited tumor recurrence in long-term experiments. Interestingly, in animals treated with CARs bearing wild-type CD3ζ, tumor recurrence was driven by the low antigen-expressing cells. Only the CAR bearing 1XX mutations demonstrated the ability to kill low antigen-expressing tumors, even when administered at low dose. Post-sacrifice analysis showed that the CAR T cells with 1XX mutations persisted longer in vivo than either 4-1BB or CD28 CAR T cells with wild-type CD3ζ.ConclusionsThese results support that the combination of targeting MUC1*, the growth factor receptor form of MUC1, with a CAR T bearing the 1XX mutations in CD3ζ has therapeutic potential for the treatment of solid tumor cancers.
Journal Article
Psychometric properties of the Alcohol Use Disorders Identification Test (AUDIT) across cross-cultural subgroups, genders, and sexual orientations: Findings from the International Sex Survey (ISS)
Despite being a widely used screening questionnaire, there is no consensus on the most appropriate measurement model for the Alcohol Use Disorders Identification Test (AUDIT). Furthermore, there have been limited studies on its measurement invariance across cross-cultural subgroups, genders, and sexual orientations.
The present study aimed to examine the fit of different measurement models for the AUDIT and its measurement invariance across a wide range of subgroups by country, language, gender, and sexual orientation.
Responses concerning past-year alcohol use from the participants of the cross-sectional International Sex Survey were considered (N = 62,943; Mage: 32.73; SD = 12.59). Confirmatory factor analysis, as well as measurement invariance tests were performed for 21 countries, 14 languages, three genders, and four sexual-orientation subgroups that met the minimum sample size requirement for inclusion in these analyses.
A two-factor model with factors describing ‘alcohol use’ (items 1–3) and ‘alcohol problems’ (items 4–10) showed the best model fit across countries, languages, genders, and sexual orientations. For the former two, scalar and latent mean levels of invariance were reached considering different criteria. For gender and sexual orientation, a latent mean level of invariance was reached.
In line with the two-factor model, the calculation of separate alcohol-use and alcohol-problem scores is recommended when using the AUDIT. The high levels of measurement invariance achieved for the AUDIT support its use in cross-cultural research, capable also of meaningful comparisons among genders and sexual orientations.
•The Alcohol Use Disorders Identification Test (AUDIT) is a widely used questionnaire.•A model with factors of alcohol use and alcohol problems showed the best fit.•High levels of measurement invariance were achieved across subgroups.•The AUDIT can capture genuine differences cross-culturally.•The AUDIT can capture genuine differences between genders and sexual orientations.
Journal Article
Visual Acuity Outcomes in Diabetic Macular Edema With Fluocinolone Acetonide 0.2 μg/Day Versus Ranibizumab Plus Deferred Laser (DRCR Protocol I)
Visual outcomes of the FAME study (0.2 μg/day fluocinolone acetonide [FAc]) and Protocol I (0.5 mg ranibizumab plus deferred laser) were compared using the area under the curve (AUC) analysis method.
Best-corrected visual acuity (BCVA) data collected during a period of 3 years of follow-up for patients enrolled in FAME or Protocol I were used to calculate AUC of the change in BCVA over a time curve.
In the overall population, there was a greater treatment effect for ranibizumab plus deferred laser compared with FAc. However, for subgroups of pseudophakic eyes, eyes with chronic diabetic macular edema (DME), and pseudophakic eyes with chronic DME, ranibizumab plus deferred laser and FAc were not found to be significantly different. The ranibizumab group received a median of 14 injections during a 36-month period compared with a mean of 1.3 injections in the FAc group.
In pseudophakic and chronic DME subgroups, FAc was comparable to ranibizumab plus deferred laser with fewer injections. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:698-706.].
Journal Article