The functional landscape of mouse gene expression

BACKGROUND: Large-scale quantitative analysis of transcriptional co-expression has been used to dissect regulatory networks and to predict the functions of new genes discovered by genome sequencing in model organisms such as yeast. Although the idea that tissue-specific expression is indicative of gene function in mammals is widely accepted, it has not been objectively tested nor compared with the related but distinct strategy of correlating gene co-expression as a means to predict gene function. RESULTS: We generated microarray expression data for nearly 40,000 known and predicted mRNAs in 55 mouse tissues, using custom-built oligonucleotide arrays. We show that quantitative transcriptional co-expression is a powerful predictor of gene function. Hundreds of functional categories, as defined by Gene Ontology 'Biological Processes', are associated with characteristic expression patterns across all tissues, including categories that bear no overt relationship to the tissue of origin. In contrast, simple tissue-specific restriction of expression is a poor predictor of which genes are in which functional categories. As an example, the highly conserved mouse gene PWP1 is widely expressed across different tissues but is co-expressed with many RNA-processing genes; we show that the uncharacterized yeast homolog of PWP1 is required for rRNA biogenesis. CONCLUSIONS: We conclude that 'functional genomics' strategies based on quantitative transcriptional co-expression will be as fruitful in mammals as they have been in simpler organisms, and that transcriptional control of mammalian physiology is more modular than is generally appreciated. Our data and analyses provide a public resource for mammalian functional genomics

Lees and Moonshine: Remembering Richard III, 1485-1635

Published version of article deposited in accordance with Sherpa Romeo guidelines. © University of Chicago Press, 2010publication-status: AcceptedNot long after Shakespeare’s birth (1564) the last witnesses to the reign of Richard III (1483-85) would have reached the end of their lives. Richard III (c. 1592) occupies a distinctive historical moment in relation to its subject – a period after the extinction of living memory, but still within the horizon of communicative memory, the period in which stories and recollections may be transmitted across multiple generations. This essay explores how memories and “postmemories” of Richard’s reign were preserved, transmitted and transformed over the course of the sixteenth century and into the seventeenth. Whilst reflecting the powerful influence of emerging contexts including the Reformation and, ultimately, Shakespeare’s play, these memories remained distinct from and sometimes at odds with textual history. They survived because they offered their bearers a resource for interpreting and resisting the predicaments of the present, from the problem of tyranny to the legacies of the Reformation

The roles of users in electric, shared and automated mobility transitions

This paper synthesizes insights from 19 peer-reviewed articles published in this Special Issue on the roles of users in shared, electric and automated mobility. While many researchers and stakeholders remain inspired by the potential low costs and societal benefits of these innovations, less is known about the real-world potential for uptake and usage. To better understand the likelihood and impacts of widespread uptake, we explore the perceptions of actual and potential users, including drivers, passengers, owners, and members, as well as other stakeholders such as pedestrians, planners, and policymakers. The Special Issue examines a range of cases, including plug-in electric vehicles, car-share and bike-share programs, ride-hailing and automated vehicles. For each innovation, we organize insights on user perceptions of benefits and drawbacks into four categories. Much of the research to date focuses on the first category, private-functional perceptions, mainly total cost of ownership (e.g., $/km), time use and comfort. Our synthesis however spans the other three categories for each innovation: private-symbolic perceptions include the potential for social signaling and communicating identity; societal-functional perceptions include GHG emissions, public safety and noise; and societal-symbolic perceptions include inspiring pro-societal behavior in others, and the potential to combat or reinforce the status quo system of “automobility”. Further, our synthesis demonstrates how different theories and methods can be more or less equipped to “see” different perception categories. We also summarize findings regarding the characteristics of early users, as well as practical insights for strategies and policies seeking societally-beneficial outcomes from mass deployment of these innovations

Using focus groups to design systems science models that promote oral health equity

Background While the US population overall has experienced improvements in oral health over the past 60 years, oral diseases remain among the most common chronic conditions across the life course. Further, lack of access to oral health care contributes to profound and enduring oral health inequities worldwide. Vulnerable and underserved populations who commonly lack access to oral health care include racial/ethnic minority older adults living in urban environments. The aim of this study was to use a systematic approach to explicate cause and effect relationships in creating a causal map, a type of concept map in which the links between nodes represent causality or influence. Methods To improve our mental models of the real world and devise strategies to promote oral health equity, methods including system dynamics, agent-based modeling, geographic information science, and social network simulation have been leveraged by the research team. The practice of systems science modeling is situated amidst an ongoing modeling process of observing the real world, formulating mental models of how it works, setting decision rules to guide behavior, and from these heuristics, making decisions that in turn affect the state of the real world. Qualitative data were obtained from focus groups conducted with community-dwelling older adults who self-identify as African American, Dominican, or Puerto Rican to elicit their lived experiences in accessing oral health care in their northern Manhattan neighborhoods. Results The findings of this study support the multi-dimensional and multi-level perspective of access to oral health care and affirm a theorized discrepancy in fit between available dental providers and patients. The lack of information about oral health at the community level may be compromising the use and quality of oral health care among racial/ethnic minority older adults. Conclusions Well-informed community members may fill critical roles in oral health promotion, as they are viewed as highly credible sources of information and recommendations for dental providers. The next phase of this research will involve incorporating the knowledge gained from this study into simulation models that will be used to explore alternative paths toward improving oral health and health care for racial/ethnic minority older adults

COVID-19 Convalescent Plasma Therapy Decreases Inflammatory Cytokines: A Randomized Controlled Trial

This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity

Dynamics of Inflammatory Responses After SARS-CoV-2 Infection by Vaccination Status in the USA: A Prospective Cohort Study

BACKGROUND: Cytokines and chemokines play a critical role in the response to infection and vaccination. We aimed to assess the longitudinal association of COVID-19 vaccination with cytokine and chemokine concentrations and trajectories among people with SARS-CoV-2 infection. METHODS: In this longitudinal, prospective cohort study, blood samples were used from participants enrolled in a multi-centre randomised trial assessing the efficacy of convalescent plasma therapy for ambulatory COVID-19. The trial was conducted in 23 outpatient sites in the USA. In this study, participants (aged ≥18 years) were restricted to those with COVID-19 before vaccination or with breakthrough infections who had blood samples and symptom data collected at screening (pre-transfusion), day 14, and day 90 visits. Associations between COVID-19 vaccination status and concentrations of 21 cytokines and chemokines (measured using multiplexed sandwich immunoassays) were examined using multivariate linear mixed-effects regression models, adjusted for age, sex, BMI, hypertension, diabetes, trial group, and COVID-19 waves (pre-alpha or alpha and delta). FINDINGS: Between June 29, 2020, and Sept 30, 2021, 882 participants recently infected with SARS-CoV-2 were enrolled, of whom 506 (57%) were female and 376 (43%) were male. 688 (78%) of 882 participants were unvaccinated, 55 (6%) were partly vaccinated, and 139 (16%) were fully vaccinated at baseline. After adjusting for confounders, geometric mean concentrations of interleukin (IL)-2RA, IL-7, IL-8, IL-15, IL-29 (interferon-λ), inducible protein-10, monocyte chemoattractant protein-1, and tumour necrosis factor-α were significantly lower among the fully vaccinated group than in the unvaccinated group at screening. On day 90, fully vaccinated participants had approximately 20% lower geometric mean concentrations of IL-7, IL-8, and vascular endothelial growth factor-A than unvaccinated participants. Cytokine and chemokine concentrations decreased over time in the fully and partly vaccinated groups and unvaccinated group. Log INTERPRETATION: Initially and during recovery from symptomatic COVID-19, fully vaccinated participants had lower concentrations of inflammatory markers than unvaccinated participants suggesting vaccination is associated with short-term and long-term reduction in inflammation, which could in part explain the reduced disease severity and mortality in vaccinated individuals. FUNDING: US Department of Defense, National Institutes of Health, Bloomberg Philanthropies, State of Maryland, Mental Wellness Foundation, Moriah Fund, Octapharma, HealthNetwork Foundation, and the Shear Family Foundation

Establishment and characterization of a new human pancreatic adenocarcinoma cell line with high metastatic potential to the lung

<p>Abstract</p> <p>Background</p> <p>Pancreatic cancer is still associated with devastating prognosis. Real progress in treatment options has still not been achieved. Therefore new models are urgently needed to investigate this deadly disease. As a part of this process we have established and characterized a new human pancreatic cancer cell line.</p> <p>Methods</p> <p>The newly established pancreatic cancer cell line PaCa 5061 was characterized for its morphology, growth rate, chromosomal analysis and mutational analysis of the K-<it>ras</it>, EGFR and p53 genes. Gene-amplification and RNA expression profiles were obtained using an Affymetrix microarray, and overexpression was validated by IHC analysis. Tumorigenicity and spontaneous metastasis formation of PaCa 5061 cells were analyzed in pfp^-/-/rag2^-/-mice. Sensitivity towards chemotherapy was analysed by MTT assay.</p> <p>Results</p> <p>PaCa 5061 cells grew as an adhering monolayer with a doubling time ranging from 30 to 48 hours. M-FISH analyses showed a hypertriploid complex karyotype with multiple numerical and unbalanced structural aberrations. Numerous genes were overexpressed, some of which have previously been implicated in pancreatic adenocarcinoma (GATA6, IGFBP3, IGFBP6), while others were detected for the first time (MEMO1, RIOK3). Specifically highly overexpressed genes (fold change > 10) were identified as EGFR, MUC4, CEACAM1, CEACAM5 and CEACAM6. Subcutaneous transplantation of PaCa 5061 into pfp^-/-/rag2^-/-mice resulted in formation of primary tumors and spontaneous lung metastasis.</p> <p>Conclusion</p> <p>The established PaCa 5061 cell line and its injection into pfp^-/-/rag2^-/-mice can be used as a new model for studying various aspects of the biology of human pancreatic cancer and potential treatment approaches for the disease.</p

Opera and Hypnosis: Victor Maurel’s Experiments with Verdi’s Otello

One day in his private home on the avenue Bugeaud, in Paris’s sixteenth arrondissement, the famous baritone Victor Maurel hosted a meeting which combined music with hypnotism of a young woman

Vocal Culture in the Age of Laryngoscopy

For several months beginning in 1884, readers of Life, Science, Health, the Atlantic Monthly and similar magazines would have encountered half-page advertisements for a newly patented medical device called the ‘ammoniaphone’ (Figure 2.1). Invented and promoted by a Scottish doctor named Carter Moffat and endorsed by the soprano Adelina Patti, British Prime Minister William Gladstone and the Princess of Wales, the ammoniaphone promised a miraculous transformation in the voices of its users. It was recommended for ‘vocalists, clergymen, public speakers, parliamentary men, readers, reciters, lecturers, leaders of psalmody, schoolmasters, amateurs, church choirs, barristers, and all persons who have to use their voices professionally, or who desire to greatly improve their speaking or singing tones’. Some estimates indicated that Moffat sold upwards of 30,000 units, yet the ammoniaphone was a flash in the pan as far as such things go, fading from public view after 1886