Measuring mitochondrial respiration in vivo: From mouse to human

Introduction: The mitochondrial energy ecosystem can be non-invasively interrogated in photoreceptors by combing a clinical tool, optical coherence tomography (OCT), with a mitochondrial protonophore (2,4 dinitrophenol, DNP). It remains unclear if only supra-clinical doses of DNP will be useful for mouse studies or if lower but clinically relevant doses of DNP would facilitate translation from mice to humans. Methods: The experiment was a paired longitudinal design that took place over 2 days. On day 1, C57BL/6J mice were overnight dark adapted, then light-adapted for 5 h before OCT examination before regaining consciousness; a similar procedure was followed on day 2 but mice were injected IP with either saline or an acceptable human dose of DNP (0.5 mg/kg) 1 hour before OCT examination. Pre- and post-injection retinal laminae thickness were compared for evidence of toxicity. In particular, we measured the external limiting membrane – retinal pigment epithelium to look for thinning between day 1 and 2, which has a confirmed basis in DNP modulation of rod photoreceptor mitochondrial respiration upstream based on pH-triggering of RPE co-transporter-based water efflux. Results: Compared to uninjected controls, saline evoked no changes in retina layer thickness between days 1 and 2. On the other hand, a clinical dose of DNP caused a reduction in ELM-RPE thickness in the absence of any other changes in retinal layer thickness, a finding consistent with increased mitochondrial respiration. Conclusions: The promising results herein raise the possibility that combining a low dose of DNP with a standard clinical imaging tool will facilitate first-in-kind measurements of neuronal mitochondria in patients suffering from a range of diseases and morbidities

Share of Wallet in Loyalty Research: Issues and a Methodology to Address Them

In a competitive market environment, share of wallet is a key measure for customer relationship management. Share of wallet analysis enables the firm to be more proactive in their ability to target customers to increase additional spending. Although share of wallet is important as a measure of customer loyalty, there is a dearth of research which focuses on share of wallet per se. In this paper, we briefly review the share of wallet literature in the context of its value to loyalty researchers. We illustrate some issues regarding share of wallet in identifying loyalty and then discuss the development of a methodology to alleviate the issues by introducing an adjusted share of wallet approach, “Share of Wallet Index” (SOWI). SOWI is calculated by multiplying by the square root of the percent that each customer is above and below the median spend in the category times the raw share of wallet measure. The SOWI approach offers a useful tradeoff between modeling total dollars and modeling raw share of wallet by taking into account both category spend and category share. It also contributes to the literature on customer relationship management and loyalty and advances the empirical analysis on the customer loyalty behavior. This research provides several managerial implications. First, this share of wallet index may help firms to identify additional revenue opportunities when more effort is used with specific customers. Second, firms can understand their relative competitive positions in the market place. We discuss limitations and future research opportunities

The role of interface organizations in science communication and understanding

“Interface” organizations are groups created to foster the use of science in environmental policy, management, and education. Here we compare interface organizations that differ in spatial scale, modes of operation, and intended audience to illustrate their diversity and importance in promoting the application of science to environmental issues. There has been exciting recent growth in the nature and extent of activities by interface organizations and in new methods for science communication and engagement. These developments can help scientists – who face personal and institutional challenges when attempting to convey the results of their research to various audiences – interact with society on specific issues in specific places, and with a wide range of non-traditional audiences. The ongoing mission for these organizations should be to move beyond simply increasing awareness of environmental problems to the creation of solutions that result in genuine environmental improvements

The role of interface organizations in science communication and understanding

“Interface” organizations are groups created to foster the use of science in environmental policy, management, and education. Here we compare interface organizations that differ in spatial scale, modes of operation, and intended audience to illustrate their diversity and importance in promoting the application of science to environmental issues. There has been exciting recent growth in the nature and extent of activities by interface organizations and in new methods for science communication and engagement. These developments can help scientists – who face personal and institutional challenges when attempting to convey the results of their research to various audiences – interact with society on specific issues in specific places, and with a wide range of non‐traditional audiences. The ongoing mission for these organizations should be to move beyond simply increasing awareness of environmental problems to the creation of solutions that result in genuine environmental improvements

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Using detrending to assess SARS-CoV-2 wastewater loads as a leading indicator of fluctuations in COVID-19 cases at fine temporal scales: Correlations across twenty sewersheds in North Carolina

Wastewater surveillance emerged during the COVID-19 pandemic as a novel strategy for tracking the burden of illness in communities. Previous work has shown that trends in wastewater SARS-CoV-2 viral loads correlate well with reported COVID-19 case trends over longer time periods (i.e., months). We used detrending time series to reveal shorter sub-trend patterns (i.e., weeks) to identify leads or lags in the temporal alignment of the wastewater/case relationship. Daily incident COVID-19 cases and twice-weekly wastewater SARS-CoV-2 viral loads measured at 20 North Carolina sewersheds in 2021 were detrended using smoothing ranges of ∞, 16, 8, 4 and 2 weeks, to produce detrended cases and wastewater viral loads at progressively finer time scales. For each sewershed and smoothing range, we calculated the Spearman correlation between the cases and the wastewater viral loads with offsets of -7 to +7 days. We identified a conclusive lead/lag relationship at 15 of 20 sewersheds, with detrended wastewater loads temporally leading detrended COVID-19 cases at 11 of these sites. For the 11 leading sites, the correlation between wastewater loads and cases was greatest for wastewater loads sampled at a median lead time of 6 days before the cases were reported. Distinct lead/lag relationships were the most pronounced after detrending with smoothing ranges of 4–8 weeks, suggesting that SARS-CoV-2 wastewater viral loads can track fluctuations in COVID-19 case incidence rates at fine time scales and may serve as a leading indicator in many settings. These results could help public health officials identify, and deploy timely responses in, areas where cases are increasing faster than the overall pandemic trend

Towards an ethical ecology of international service learning

International Service-Learning (ISL) is a pedagogical activity that seeks to blend student learning with community engagement overseas and the development of a more just society. ISL programmes have grown as educational institutions and non-governmental organisations have sought to achieve the goal of developing ‘global citizens’. However, Service Learning (SL) in general and International Service-Learning (ISL) in particular remain deeply under theorised. These educational initiatives provide policy makers with a practical response to their quest for a ‘Big Society’and present alluring pedagogical approaches for Universities as they react to reforms in Higher Education and seek to enhance both the student learning experience and graduate employability. After outlining the development of ISL in policy and practice, this paper draws on the rich tradition of ISL at one British university to argue that ISL is a form of engagement that has the potential to be ethical in character although we identify a number of factors that militate against this. Our contention is that ISL which promotes rationaland instrumental learning represents a deficit model and we therefore conceptualise ISL here as a transformative learning experience that evinces distinctly aesthetic and even spiritual dimensions. Upon this theoretical groundwork we lay the foundations for conceptualizing ISL in ways that ensure its ethical integrity