ADAR1 and its implications in cancer development and treatment.

The family of adenosine deaminases acting on RNA (ADARs) regulates global gene expression output by catalyzing adenosine-to-inosine (A-to-I) editing of double-stranded RNA (dsRNA) and through interacting with RNA and other proteins. ADARs play important roles in development and disease, including an increasing connection to cancer progression. ADAR1 has demonstrated a largely pro-oncogenic role in a growing list of cancer types, and its function in cancer has been attributed to diverse mechanisms. Here, we review existing literature on ADAR1 biology and function, its roles in human disease including cancer, and summarize known cancer-associated phenotypes and mechanisms. Lastly, we discuss implications and outstanding questions in the field, including strategies for targeting ADAR1 in cancer.

Fgf, Hh, and pax2a differentially regulate expression of pax5 and pou3f3b in vestibular and auditory maculae in the zebrafish otic vesicle.

BACKGROUND: The vertebrate inner ear contains distinct sensory epithelia specialized for auditory or vestibular function. In zebrafish, the first sensory epithelia form at opposite ends of the otic vesicle and are functionally distinct: the anterior utricular macula is essential for vestibular function whereas the posterior saccular macula is critical for hearing. Mechanisms distinguishing these maculae are not clear. Here, we examined the effects of manipulating Fgf or Hh on expression of pax5 and pou3f3b, unique markers of utricular and saccular identity. We also examined the roles of pax2a and atoh1a/b, early regulators of sensory specification. RESULTS: fgf3 and fgf8a were uniquely required for pax5 and pou3f3b, respectively. Elevating Fgf or blocking Hh expanded expression of pax5 but repressed pou3f3b, while blocking Fgf had the opposite effect. Blocking sensory specification did not affect pax5 or pou3f3b, but both markers were lost in pax2a-/- mutants. Maintenance of pax2a expression requires Fgf, Hh and Pax2a itself. CONCLUSION: Specification of utricular identity requires high Fgf and is repressed by Hh, whereas saccular identity requires Hh plus low Fgf. pax2a acts downstream of Fgf and Hh to maintain both fates. Comparison with mouse suggests this may reflect a broadly conserved developmental mechanism.

An ADAR1-dependent RNA editing event in the cyclin-dependent kinase CDK13 promotes thyroid cancer hallmarks.

BACKGROUND: Adenosine deaminases acting on RNA (ADARs) modify many cellular RNAs by catalyzing the conversion of adenosine to inosine (A-to-I), and their deregulation is associated with several cancers. We recently showed that A-to-I editing is elevated in thyroid tumors and that ADAR1 is functionally important for thyroid cancer cell progression. The downstream effectors regulated or edited by ADAR1 and the significance of ADAR1 deregulation in thyroid cancer remain, however, poorly defined. METHODS: We performed whole transcriptome sequencing to determine the consequences of ADAR1 deregulation for global gene expression, RNA splicing and editing. The effects of gene silencing or RNA editing were investigated by analyzing cell viability, proliferation, invasion and subnuclear localization, and by protein and gene expression analysis. RESULTS: We report an oncogenic function for CDK13 in thyroid cancer and identify a new ADAR1-dependent RNA editing event that occurs in the coding region of its transcript. CDK13 was significantly over-edited (c.308A > G) in tumor samples and functional analysis revealed that this editing event promoted cancer cell hallmarks. Finally, we show that CDK13 editing increases the nucleolar abundance of the protein, and that this event might explain, at least partly, the global change in splicing produced by ADAR1 deregulation. CONCLUSIONS: Overall, our data support A-to-I editing as an important pathway in cancer progression and highlight novel mechanisms that might be used therapeutically in thyroid and other cancers.

Harsh and Sweet Sensations Predict Acute Liking of Electronic Cigarettes, but Flavor Does Not Affect Acute Nicotine Intake: A Pilot Laboratory Study in Men.

INTRODUCTION: Electronic cigarette use is increasing in popularity, and thousands of flavors are available. Adolescent vaping rates in the United States have nearly doubled in the past year. Unlike combustible tobacco, added flavors are not currently regulated for some types of electronic cigarette products. Here, we investigated the role of flavor in electronic cigarette liking and acute intake. METHODS: Men (n = 39) aged 18-45 vaped in a controlled laboratory setting after being randomized to one of four e-liquids: 6 mg nicotine/mL cherry, 18 mg/mL cherry, 6 mg/mL chocolate, or 18 mg/mL chocolate. They completed several questionnaires, and vaped ad libitum for 10 minutes. After the first puff, participants rated sensations (sweetness, bitterness, coolness, harshness/irritation) on general labeled magnitude scales (gLMS) and rated overall liking on a generalized hedonic scale. Once the 10-minute session ended, participants made another set of ratings. RESULTS: Liking was generally stable across the vaping session and liking varied substantially across the four conditions. Across all conditions, sensory ratings predicted liking: harshness/irritation was negatively associated with first puff liking, whereas perceived sweetness was positively associated with first puff liking. First puff liking associated with increased amount of e-liquid vaped, but not total nicotine intake. Participants appeared to titrate their nicotine intake regardless of assigned condition. CONCLUSION: Flavored e-liquids affect acute liking ratings, but not acute nicotine intake. IMPLICATIONS: These data suggest individuals who regularly vape may titrate their nicotine intake, regardless of flavor, and contrary to expectations, acute liking did not predict total nicotine intake. However, more-liked flavors may potentially make higher nicotine levels more tolerable by adding pleasant sensations directly, rather than by perceptual masking that reduces aversive sensations.

Economics at the FCC 2020-21: Closing the Connectivity Gap, COVID-19 and Telehealth, Spectrum Auctions, Communications Marketplace Report, and Economic Research.

The U.S. Federal Communications Commission is responsible for regulation in the communications marketplace and for management of the nation's non-federal radio frequency spectrum. During the past year, FCC economists assisted in the development of initiatives that were aimed at closing the connectivity gap which proved especially critical in light of the COVID-19 pandemic; contributed to the Commission's extensive responses to COVID-19; were involved in various spectrum auctions; evaluated competition in the communications marketplace in the 2020 Communications Marketplace Report; and published a series of working papers.

Economics at the FCC 2019-2020: Spectrum Policy, Universal Service, Inmate Calling Services, and Telehealth.

The U.S. Federal Communications Commission is responsible for regulation in the communications marketplace and for management of the nation's non-federal radio frequency spectrum. During the past year, FCC economists helped develop efficient mechanisms for making available more flexible-use spectrum for the deployment of advanced broadband technologies; developed two new universal service funding mechanisms that aim to close the digital broadband divide; and, through careful analysis of firm cost data, contributed to a renewed effort by the Commission to develop price caps for interstate calls on prison inmate calling services. FCC economists also contributed to the Commission's extensive response to COVID-19.

Self-reported Smoking Status, TAS2R38 Variants, and Propylthiouracil Phenotype: An Exploratory Crowdsourced Cohort Study.

TAS2R38 gene variants, which confer sensitivity to specific bitter tastants (e.g., 6-n-propylthiouracil), have been repeatedly associated with lower alcohol use via greater bitterness perception, but research exploring TAS2R38 variation in relation to smoking shows mixed results. In both, the working hypothesis is that 1 or more copies of the functional allele increases bitterness and may provide a barrier to early use. Such a barrier to initiation may, conceivably, manifest as differential rates of current use across diplotypes. Here, an age-diverse convenience sample (n = 886) of Denver Museum of Nature and Science guests was used to explore cross-sectional relationships between TAS2R38 diplotype, self-reported tobacco use (current, former, never smokers), and a rapid measure of 6-n-propylthiouracil phenotype (bitterness of filter paper discs). TAS2R38 diplotypes were determined by Sanger sequencing. After excluding rare diplotypes, data from 814 participants were analyzed. A mix of current (~10%), former (25%), and never smokers (65%) were included. As expected, there was a relationship between TAS2R38 diplotype and 6-n-propylthiouracil bitterness. However, contrary to our hypothesis, there was no evidence of a relationship between diplotype and smoker status among participants with common TAS2R38 diplotypes. Notably, we observed a relationship between of 6-n-propylthiouracil bitterness and smoking status, but the effect was opposite of what was expected: current smokers perceived higher (not lower) bitterness than never smokers. When all the various factors (diplotype, age, sex, and smoking status) were included in ANOVA, all remained predictive of 6-n-propylthiouracil bitterness. Reasons for greater phenotypic bitterness among current smokers are unknown and merit further study.

Units of Distinction: Creating a Blueprint for Recognition of High-Performing Medical-Surgical Nursing Units.

BACKGROUND: Hospital medical-surgical (M/S) nursing units are responsible for up to 28 million encounters annually, yet receive little attention from professional organizations and national initiatives targeted to improve quality and performance. OBJECTIVE: We sought to develop a framework recognizing high-performing units within our large hospital system. METHODS: This was a retrospective data analysis of M/S units throughout a 168-hospital system. Measures represented patient experience, employee engagement, staff scheduling, nursing-sensitive patient outcomes, professional practices, and clinical process measures. RESULTS: Four hundred ninety units from 129 hospitals contributed information to test the framework. A manual scoring system identified the top 5% and recognized them as a "Unit of Distinction." Secondary analyses with machine learning provided validation of the proposed framework. CONCLUSIONS: Similar to external recognition programs, this framework and process provide a holistic evaluation useful for meaningful recognition and lay the groundwork for benchmarking in improvement efforts.

The effect of litter separation on methamphetamine-conditioned place preference in post-partum dams.

Methamphetamine (METH) abuse among women has recently increased to levels comparable to those observed in men. Although studies using animal models of addiction have begun to include more female subjects, examination of the effects of drugs of abuse on post-partum females is currently lacking. This is especially important in light of the significant hormonal and neurobiological changes that accompany pregnancy and rearing experiences. Furthermore, stress in a known factor in addiction vulnerability and the post-partum experience in the clinical population can be highly stressful. Here, we utilized the conditioned place preference paradigm to investigate the conditioned rewarding effects of METH either in virgin rats or in dams exposed to brief separation (15 min) or long separation (180 min) from the litter. We found that females in the brief separation group showed significantly greater METH conditioned place preference compared with both the long separation and virgin groups. No differences were found in locomotor activity during the conditioning sessions. These findings suggest that peripartum experience and brief litter separation may enhance the rewarding effects of METH.

"They Treat you a Different Way:" Public Insurance, Stigma, and the Challenge to Quality Health Care.

Under the Affordable Care Act, Medicaid Expansion programs are extending Medicaid eligibility and increasing access to care. However, stigma associated with public insurance coverage may importantly affect the nature and content of the health care beneficiaries receive. In this paper, we examine the health care stigma experiences described by a group of low-income public insurance beneficiaries. They perceive stigma as manifest in poor quality care and negative interpersonal interactions in the health care setting. Using an intersectional approach, we found that the stigma of public insurance was compounded with other sources of stigma including socioeconomic status, race, gender, and illness status. Experiences of stigma had important implications for how subjects evaluated the quality of care, their decisions impacting continuity of care, and their reported ability to access health care. We argue that stigma challenges the quality of care provided under public insurance and is thus a public health issue that should be addressed in Medicaid policy.

Electronic Health Records and the Disappearing Patient.

With rapid consolidation of American medicine into large-scale corporations, corporate strategies are coming to the forefront in health care delivery, requiring a dramatic increase in the amount and detail of documentation, implemented through use of electronic health records (EHRs). EHRs are structured to prioritize the interests of a myriad of political and corporate stakeholders, resulting in a complex, multi-layered, and cumbersome health records system, largely not directly relevant to clinical care. Drawing on observations conducted in outpatient specialty clinics, we consider how EHRs prioritize institutional needs manifested as a long list of requisites that must be documented with each consultation. We argue that the EHR enforces the centrality of market principles in clinical medicine, redefining the clinician's role to be less of a medical expert and more of an administrative bureaucrat, and transforming the patient into a digital entity with standardized conditions, treatments, and goals, without a personal narrative.

Counterproductive Consequences of a Conservative Ideology: Medicaid Expansion and Personal Responsibility Requirements.

Medicaid expansion, a key part of the Affordable Care Act, has been opposed by conservative politicians despite its fiscal and public health benefits. In response, some Republican-led states have expanded Medicaid with new reforms, including requirements for cost sharing and behavioral incentives, that promote conservative political values tied to an ideology of personal responsibility. We examine this trend using Michigan's Medicaid expansion as a case example. We explore the origins, evidence base, and possible consequences of these reforms. We argue that these reforms prioritize ideology over sound public health knowledge, deflecting attention away from the social, economic, and structural factors that influence the health of the poor, and may ultimately contribute to counterproductive public health and fiscal outcomes.

E-learning and research experience exchange in the online setting of student peer mentor network during COVID-19 pandemic and beyond: A laboratory case study.

For close to 2 years, we have witnessed the impacts of the SARS-CoV-2 pandemic on research at several different levels. Among the list, limited access to laboratory-based training for undergraduate students prevented this cohort from gaining exposure to the realities of a research laboratory at a critical time in training when they may have found motivation in this area as a career. COVID exposed a weakness in our training pipeline; an extreme dependency on face-to-face training that threatened to create a void in the research talent needed to replenish the scientific community every year. In the classroom, we witnessed a revolution of e-learning based approaches that could be rapidly implemented based on existing footprints. Out of necessity, our laboratory developed and implemented an e-learning model of an undergraduate peer mentor network that provides a knowledge and experience exchange platform between students with different levels of research experience. Implementation of the platform was to aid students with gaining knowledge in multiple aspects of scientific research and hands-on work in a research laboratory. The collaboration between the students of the network was aimed at not only advancing the theoretical and practical research experience, but also at developing feedback implementation and practicing "soft skills" critical for teamwork and leadership. Herein, we present an overview of the model along with survey responses of the students participating in the peer mentor network. We have found that peer delivery of practical benchwork both via scientific presentations and visualized experiments, reduced the time of training and the amount of staff assistance needed when students returned to the bench. Furthermore, this model accelerated student independence in laboratory work and increased research interest overall. In summary, the model of a peer mentor network has the potential to serve as a training platform and as a customized tool, supplementing research laboratory training at the undergraduate level beyond the pandemic.

On a Structural Similarity Index Approach for Floating-Point Data.

Data visualization is typically a critical component of post-processing analysis workflows for floating-point output data from large simulation codes, such as global climate models. For example, images are often created from the raw data as a means for evaluation against a reference dataset or image. While the popular Structural Similarity Index Measure (SSIM) is a useful tool for such image comparisons, generating large numbers of images can be costly when simulation data volumes are substantial. In fact, computational cost considerations motivated our development of an alternative to the SSIM, which we refer to as the Data SSIM (DSSIM). The DSSIM is conceptually similar to the SSIM, but can be applied directly to the floating-point data as a means of assessing data quality. We present the DSSIM in the context of quantifying differences due to lossy compression on large volumes of simulation data from a popular climate model. Bypassing image creation results in a sizeable performance gain for this case study. In addition, we show that the DSSIM is useful in terms of avoiding plot-specific (but data-independent) choices that can affect the SSIM. While our work is motivated by and evaluated with climate model output data, the DSSIM may prove useful for other applications involving large volumes of simulation data.

North Atlantic subtropical mode water formation controlled by Gulf Stream fronts.

The North Atlantic Ocean hosts the largest volume of global subtropical mode waters (STMWs) in the world, which serve as heat, carbon and oxygen silos in the ocean interior. STMWs are formed in the Gulf Stream region where thermal fronts are pervasive and result in feedback with the atmosphere. However, their roles in STMW formation have been overlooked. Using eddy-resolving global climate simulations, we find that suppressing local frontal-scale ocean-to-atmosphere (FOA) feedback leads to STMW formation being reduced almost by half. This is because FOA feedback enlarges STMW outcropping, attributable to the mixed layer deepening associated with cumulative excessive latent heat loss due to higher wind speeds and greater air-sea humidity contrast driven by the Gulf Stream fronts. Such enhanced heat loss overshadows the stronger restratification induced by vertical eddies and turbulent heat transport, making STMW colder and heavier. With more realistic representation of FOA feedback, the eddy-present/rich coupled global climate models reproduce the observed STMWs much better than the eddy-free ones. Such improvement in STMW production cannot be achieved, even with the oceanic resolution solely refined but without coupling to the overlying atmosphere in oceanic general circulation models. Our findings highlight the need to resolve FOA feedback to ameliorate the common severe underestimation of STMW and associated heat and carbon uptakes in earth system models.

CDK2 inhibition disorders centrosome stoichiometry and alters cellular outcomes in aneuploid cancer cells.

Cyclin-dependent Kinase 2 (CDK2) inhibition prevents supernumerary centrosome clustering. This causes multipolarity, anaphase catastrophe and apoptotic death of aneuploid cancers. This study elucidated how CDK2 antagonism affected centrosome stoichiometry. Focused ion beam scanning electron microscopy (FIB-SEM) and immunofluorescent imaging were used. Studies interrogated multipolar mitosis after pharmacologic or genetic repression of CDK2. CDK2/9 antagonism with CYC065 (Fadraciclib)-treatment disordered centrosome stoichiometry in aneuploid cancer cells, preventing centrosome clustering. This caused ring-like chromosomes or multipolar cancer cells to form before onset of cell death. Intriguingly, CDK2 inhibition caused a statistically significant increase in single centrioles rather than intact centrosomes with two centrioles in cancer cells having chromosome rings or multipolarity. Statistically significant alterations in centrosome stoichiometry were undetected in other mitotic cancer cells. To confirm this pharmacodynamic effect, CDK2 but not CDK9 siRNA-mediated knockdown augmented cancer cells with chromosome ring or multipolarity formation. Notably, engineered gain of CDK2, but not CDK9 expression, reversed emergence of cancer cells with chromosome rings or multipolarity, despite CYC065-treatment. In marked contrast, CDK2 inhibition of primary human alveolar epithelial cells did not confer statistically significant increases of cells with ring-like chromosomes or multipolarity. Hence, CDK2 antagonism caused differential effects in malignant versus normal alveolar epithelial cells. Translational relevance was confirmed by CYC065-treatment of syngeneic lung cancers in mice. Mitotic figures in tumors exhibited chromosome rings or multipolarity. Thus, CDK2 inhibition preferentially disorders centrosome stoichiometry in cancer cells. Engaging this disruption is a strategy to explore against aneuploid cancers in future clinical trials.

Flavor science in the context of research on electronic cigarettes.

Thousands start smoking or vaping daily, despite long-standing efforts by public health authorities to curb initiation and use of nicotine containing products. Over the last 15 years, use of electronic nicotine delivery systems has increased dramatically, with a diverse range of products on the market, including pod-based, disposable, and refillable electronic cigarettes (eCigs). Originally intended for harm reduction and smoking cessation, eCigs may encourage nicotine use among never smokers, given the vast range of appealing flavors that are available. To better understand abuse liability and to facilitate appropriate regulations, it is crucial to understand the science of flavor, and flavor perception within the context of eCig use. Here, we (a) provide a brief primer on chemosensory perception and flavor science for addiction and nicotine researchers, and (b) highlight existing some literature regarding flavor and nicotine use, with specific attention given to individual differences in perception, and interaction between different sensory modalities that contribute to flavor. Dramatic increases in use of eCigs highlights the importance of flavor science in contemporary addiction research, both with regards to public health and regulatory efforts. Other recent work summarizes findings on flavored e-liquids and eCig use, but none have focused explicitly on chemosensory processes or flavor perception as they relate to appeal and use of such products. We argue flavor science needs to be considered as perceptual and behavioral phenomena, and not merely from analytical, toxicological and pharmacological perspectives; we help address this gap here.

The Course of ADHD during Pregnancy.

OBJECTIVE: The aim of this study was to characterize the course of ADHD during pregnancy. METHOD: Women ages 18 to 45 were followed prospectively at <20 weeks, 24 weeks, and 36 weeks pregnant. Three groups emerged: women who discontinued, maintained, or adjusted their ADHD medications. ADHD symptoms were recorded using the AISRS. Anxiety, depression, stress, and functional impairment were monitored. RESULTS: A total of 25 women with ADHD were eligible for analysis. No significant difference observed between three groups in AISRS scores. Significant differences found between medication discontinuers vs adjusters for both mood and family functioning (EPDS, 5.3, p < .0001; WFIRS, 3.3, p = .0309). Significant differences also found between discontinuers vs maintainers for mood and family functioning (EPDS, 4.98, p = .0009; WFIRS, 3.09, p = .0197). CONCLUSION: This preliminary study provides novel insight into the course of ADHD during pregnancy, underscoring mood and family functioning as critical domains that may contribute to growing use of psychostimulants during pregnancy.

Transcriptome Profiling of ADAR1 Targets in Triple-Negative Breast Cancer Cells Reveals Mechanisms for Regulating Growth and Invasion.

ADARs catalyze adenosine-to-inosine (A-to-I) editing of double-stranded RNA and regulate global gene expression output through interactions with RNA and other proteins. ADARs play important roles in development and disease, and previous work has shown that ADAR1 is oncogenic in a growing list of cancer types. Here we show that ADAR1 is a critical gene for triple-negative breast cancer cells, as ADAR1 loss results in reduced growth (viability and cell cycle progression), invasion, and mammosphere formation. Whole transcriptome sequencing analyses demonstrate that ADAR1 regulates both coding and noncoding targets by altering gene expression level, A-to-I editing, and splicing. We determine that a recoding edit in filamin B (FLNB chr3:58156064) reduces the tumor suppressive activities of the protein to promote growth and invasion. We also show that several tumor suppressor miRNAs are upregulated upon ADAR1 loss and suppress cell-cycle progression and invasion. This work describes several novel mechanisms of ADAR1-mediated oncogenesis in triple-negative breast cancer, providing support to strategies targeting ADAR1 in this aggressive cancer type that has few treatment options. IMPLICATIONS: Targeting ADAR1 and thus downstream FLNB editing and miRNA regulation represents a possible novel therapeutic strategy in triple-negative breast cancer.

Fitted filtration efficiency and breathability of 2-ply cotton masks: Identification of cotton consumer categories acceptable for home-made cloth mask construction.

The objective of this study was to characterize commercially-available cotton fabrics to determine their suitability as materials for construction of cloth masks for personal and public use to reduce infectious disease spread. The study focused on cottons because of their widespread availability, moderate performance and they are recommended for inclusion in home-made masks by international health authorities. Fifty-two cottons were analyzed by electron microscopy to determine fabric characteristics and fabric weights. Sixteen fabrics were selected to test for breathability and to construct 2-ply cotton masks of a standard design to use in quantitative fit testing on a human participant. Cotton mask fitted filtration efficiencies (FFEs) for 0.02-1 µm ambient and aerosolized sodium chloride particles ranged from 40 to 66% compared with the mean medical mask FFE of 55±2%. Pressure differentials across 2-ply materials ranged from 0.57 to > 12 mm H2O/cm2 on samples of equal surface area with 6 of 16 materials exceeding the recommended medical mask limit. Models were calibrated to predict 2-ply cotton mask FFEs and differential pressures for each fabric based on pore characteristics and fabric weight. Models indicated cotton fabrics from 6 of 9 consumer categories can produce cloth masks with adequate breathability and FFEs equivalent to a medical mask: T-shirt, fashion fabric, mass-market quilting cotton, home décor fabric, bed sheets and high-quality quilting cotton. Masks from one cloth mask and the medical mask were re-tested with a mask fitter to distinguish filtration from leakage. The fabric and medical masks had 3.7% and 41.8% leakage, respectively. These results indicate a well fitted 2-ply cotton mask with overhead ties can perform similarly to a disposable 3-ply medical mask on ear loops due primarily to the superior fit of the cloth mask which compensates for its lower material filtration efficiency.