The ethics of digital well-being: a multidisciplinary perspective

This chapter serves as an introduction to the edited collection of the same name, which includes chapters that explore digital well-being from a range of disciplinary perspectives, including philosophy, psychology, economics, health care, and education. The purpose of this introductory chapter is to provide a short primer on the different disciplinary approaches to the study of well-being. To supplement this primer, we also invited key experts from several disciplines—philosophy, psychology, public policy, and health care—to share their thoughts on what they believe are the most important open questions and ethical issues for the multi-disciplinary study of digital well-being. We also introduce and discuss several themes that we believe will be fundamental to the ongoing study of digital well-being: digital gratitude, automated interventions, and sustainable co-well-being

Tissue microarray analysis of human FRAT1 expression and its correlation with the subcellular localisation of ?-catenin in ovarian tumours

The mechanisms involved in the pathogenesis of ovarian cancer are poorly understood, but evidence suggests that aberrant activation of Wnt/?-catenin signalling pathway plays a significant role in this malignancy. However, the molecular defects that contribute to the activation of this pathway have not been elucidated. Frequently rearranged in advanced T-cell lymphomas-1 (FRAT1) is a candidate for the regulation of cytoplasmic ?-catenin. In this study, we developed in situ hybridisation probes to evaluate the presence of FRAT1 and used an anti-?-catenin antibody to evaluate by immunohistochemistry the expression levels and subcellular localisation of ?-catenin in ovarian cancer tissue microarrays. Expression of FRAT1 was found in some human normal tissues and 47% of ovarian adenocarcinomas. A total of 46% of ovarian serous adenocarcinomas were positive for FRAT1 expression. Accumulation of ?-catenin in the nucleus and/or cytoplasm was observed in 55% ovarian adenocarcinomas and in 59% of serous adenocarcinomas. A significant association was observed in ovarian serous adenocarcinomas between FRAT1 and ?-catenin expression (P<0.01). These findings support that Wnt/?-catenin signalling may be aberrantly activated through FRAT1 overexpression in ovarian serous adenocarcinomas. The mechanism behind the overexpression of FRAT1 in ovarian serous adenocarcinomas and its significance is yet to be investigated

Real-time observation of multiexcitonic states in ultrafast singlet fission using coherent 2D electronic spectroscopy.

Singlet fission is the spin-allowed conversion of a spin-singlet exciton into a pair of spin-triplet excitons residing on neighbouring molecules. To rationalize this phenomenon, a multiexcitonic spin-zero triplet-pair state has been hypothesized as an intermediate in singlet fission. However, the nature of the intermediate states and the underlying mechanism of ultrafast fission have not been elucidated experimentally. Here, we study a series of pentacene derivatives using ultrafast two-dimensional electronic spectroscopy and unravel the origin of the states involved in fission. Our data reveal the crucial role of vibrational degrees of freedom coupled to electronic excitations that facilitate the mixing of multiexcitonic states with singlet excitons. The resulting manifold of vibronic states drives sub-100 fs fission with unity efficiency. Our results provide a framework for understanding singlet fission and show how the formation of vibronic manifolds with a high density of states facilitates fast and efficient electronic processes in molecular systems.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/nchem.237

Novel Anti-bacterial Activities of β-defensin 1 in Human Platelets: Suppression of Pathogen Growth and Signaling of Neutrophil Extracellular Trap Formation

Human β-defensins (hBD) are antimicrobial peptides that curb microbial activity. Although hBD's are primarily expressed by epithelial cells, we show that human platelets express hBD-1 that has both predicted and novel antibacterial activities. We observed that activated platelets surround Staphylococcus aureus (S. aureus), forcing the pathogens into clusters that have a reduced growth rate compared to S. aureus alone. Given the microbicidal activity of β-defensins, we determined whether hBD family members were present in platelets and found mRNA and protein for hBD-1. We also established that hBD-1 protein resided in extragranular cytoplasmic compartments of platelets. Consistent with this localization pattern, agonists that elicit granular secretion by platelets did not readily induce hBD-1 release. Nevertheless, platelets released hBD-1 when they were stimulated by α-toxin, a S. aureus product that permeabilizes target cells. Platelet-derived hBD-1 significantly impaired the growth of clinical strains of S. aureus. hBD-1 also induced robust neutrophil extracellular trap (NET) formation by target polymorphonuclear leukocytes (PMNs), which is a novel antimicrobial function of β-defensins that was not previously identified. Taken together, these data demonstrate that hBD-1 is a previously-unrecognized component of platelets that displays classic antimicrobial activity and, in addition, signals PMNs to extrude DNA lattices that capture and kill bacteria

Prognostic impact of human epidermal growth factor-like receptor 2 and hormone receptor status in inflammatory breast cancer (IBC): analysis of 2,014 IBC patient cases from the California Cancer Registry

IntroductionInflammatory breast cancer (IBC) is an aggressive form of breast cancer associated with overexpression of Her2/Neu (human epidermal growth factor-like receptor 2 (HER2)) and poor survival. We investigated survival differences for IBC patient cases based on hormone receptor status and HER2 receptor status using data from the California Cancer Registry, as contrasted with locally advanced breast cancer (LABC), metastatic breast cancer (MBC) and non-T4 breast cancer.MethodsA case-only analysis of 80,099 incident female breast cancer patient cases in the California Cancer Registry during 1999 to 2003 was performed, with follow-up through March 2007. Overall survival (OS) and breast cancer-specific survival (BC-SS) were analyzed using Kaplan-Meier methods and Cox proportional hazards ratios.ResultsA total of 2,014 IBC, 1,268 LABC, 3,059 MBC, and 73,758 non-T4 breast cancer patient cases were identified. HER2+ was associated with advanced tumor stage (P < 0.0001). IBC patient cases were more likely to be HER2+ (40%) and less likely to be hormone receptor-positive (HmR+) (59%) compared with LABC (35% and 69%, respectively), MBC (35% and 74%), and non-T4 patient cases (22% and 82%). HmR+ status was associated with improved OS and BC-SS for each breast cancer subtype after adjustment for clinically relevant factors. In multivariate analysis, HER2+ (versus HER2-) status was associated with poor BC-SS for non-T4 patient cases (hazards ratio = 1.16, 95% confidence interval 1.05 to 1.28) and had a borderline significant association with improved BC-SS for IBC (hazards ratio = 0.82, 95% confidence interval = 0.68 to 0.99).ConclusionsDespite an association with advanced tumor stage, HER2+ status is not an independent adverse prognostic factor for survival among IBC patient cases

Biliary dyskinesia: a potentially unrecognized cause of abdominal pain in children

Biliary dyskinesia is defined as symptomatic biliary colic without cholelithiasis, and is diagnosed during cholescintigraphy by assessing gallbladder emptying with cholecystokinin (CCK) stimulation. Unfortunately, gallbladder emptying is not routinely assessed during cholescintigraphy in pediatric patients. The purpose of this review is to assess the effectiveness of cholecystectomy in patients with chronic abdominal pain and delayed gallbladder emptying and to assess whether these findings correlate with the histologic evidence of chronic cholecystitis. We retrospectively reviewed the medical records of all patients ( n =16) at our institution from October 1997 to August 2001 who underwent quantitative cholescintigraphy with CCK stimulation that demonstrated delayed gallbladder emptying (<35% at 60 min) and who subsequently underwent cholecystectomy. Laparoscopic cholecystectomy was performed in 16 patients with chronic abdominal pain. All 16 patients had delayed gallbladder emptying (mean ejection fraction : 15±8%, range: 3–32%). The mean age was 12±2 years (range: 8–17 years). Presenting symptoms included abdominal pain (86%), fatty food intolerance (27%), emesis (13%), and diarrhea (13%). Mean duration of abdominal pain before operation was 11±19 months (range: 2 weeks–6 years). One patient’s symptoms persisted postoperatively , but abdominal pain resolved in all other patient s. Histologic evidence of chronic cholecystitis was demonstrated in 86% of surgical specimens. Five patients underwent concurrent appendectomy , and all had normal appendiceal histology. Our experience suggests that children with chronic abdominal pain and delayed gallbladder emptying on CCK-stimulated cholescintigraphy are likely to benefit from cholecystectomy and to have histologic evidence of chronic cholecystitis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47166/1/383_2004_Article_1234.pd

Low Frequency Vibrations Disrupt Left-Right Patterning in the Xenopus Embryo

The development of consistent left-right (LR) asymmetry across phyla is a fascinating question in biology. While many pharmacological and molecular approaches have been used to explore molecular mechanisms, it has proven difficult to exert precise temporal control over functional perturbations. Here, we took advantage of acoustical vibration to disrupt LR patterning in Xenopus embryos during tightly-circumscribed periods of development. Exposure to several low frequencies induced specific randomization of three internal organs (heterotaxia). Investigating one frequency (7 Hz), we found two discrete periods of sensitivity to vibration; during the first period, vibration affected the same LR pathway as nocodazole, while during the second period, vibration affected the integrity of the epithelial barrier; both are required for normal LR patterning. Our results indicate that low frequency vibrations disrupt two steps in the early LR pathway: the orientation of the LR axis with the other two axes, and the amplification/restriction of downstream LR signals to asymmetric organs

Group A Streptococcus Secreted Esterase Hydrolyzes Platelet-Activating Factor to Impede Neutrophil Recruitment and Facilitate Innate Immune Evasion

The innate immune system is the first line of host defense against invading organisms. Thus, pathogens have developed virulence mechanisms to evade the innate immune system. Here, we report a novel means for inhibition of neutrophil recruitment by Group A Streptococcus (GAS). Deletion of the secreted esterase gene (designated sse) in M1T1 GAS strains with (MGAS5005) and without (MGAS2221) a null covS mutation enhances neutrophil ingress to infection sites in the skin of mice. In trans expression of SsE in MGAS2221 reduces neutrophil recruitment and enhances skin invasion. The sse deletion mutant of MGAS5005 (ΔsseMGAS5005) is more efficiently cleared from skin than the parent strain. SsE hydrolyzes the sn-2 ester bond of platelet-activating factor (PAF), converting biologically active PAF into inactive lyso-PAF. KM and kcat of SsE for hydrolysis of 2-thio-PAF were similar to those of the human plasma PAF acetylhydrolase. Treatment of PAF with SsE abolishes the capacity of PAF to induce activation and chemotaxis of human neutrophils. More importantly, PAF receptor-deficient mice significantly reduce neutrophil infiltration to the site of ΔsseMGAS5005 infection. These findings identify the first secreted PAF acetylhydrolase of bacterial pathogens and support a novel GAS evasion mechanism that reduces phagocyte recruitment to sites of infection by inactivating PAF, providing a new paradigm for bacterial evasion of neutrophil responses

Spatial variations in the incidence of breast cancer and potential risks associated with soil dioxin contamination in Midland, Saginaw, and Bay Counties, Michigan, USA

<p>Abstract</p> <p>Background</p> <p>High levels of dioxins in soil and higher-than-average body burdens of dioxins in local residents have been found in the city of Midland and the Tittabawassee River floodplain in Michigan. The objective of this study is threefold: (1) to evaluate dioxin levels in soils; (2) to evaluate the spatial variations in breast cancer incidence in Midland, Saginaw, and Bay Counties in Michigan; (3) to evaluate whether breast cancer rates are spatially associated with the dioxin contamination areas.</p> <p>Methods</p> <p>We acquired 532 published soil dioxin data samples collected from 1995 to 2003 and data pertaining to female breast cancer cases (<it>n </it>= 4,604) at ZIP code level in Midland, Saginaw, and Bay Counties for years 1985 through 2002. Descriptive statistics and self-organizing map algorithm were used to evaluate dioxin levels in soils. Geographic information systems techniques, the Kulldorff's spatial and space-time scan statistics, and genetic algorithms were used to explore the variation in the incidence of breast cancer in space and space-time. Odds ratio and their corresponding 95% confidence intervals, with adjustment for age, were used to investigate a spatial association between breast cancer incidence and soil dioxin contamination.</p> <p>Results</p> <p>High levels of dioxin in soils were observed in the city of Midland and the Tittabawassee River 100-year floodplain. After adjusting for age, we observed high breast cancer incidence rates and detected the presence of spatial clusters in the city of Midland, the confluence area of the Tittabawassee, and Saginaw Rivers. After accounting for spatiotemporal variations, we observed a spatial cluster of breast cancer incidence in Midland between 1985 and 1993. The odds ratio further suggests a statistically significant (<it>α </it>= 0.05) increased breast cancer rate as women get older, and a higher disease burden in Midland and the surrounding areas in close proximity to the dioxin contaminated areas.</p> <p>Conclusion</p> <p>These findings suggest that increased breast cancer incidences are spatially associated with soil dioxin contamination. Aging is a substantial factor in the development of breast cancer. Findings can be used for heightened surveillance and education, as well as formulating new study hypotheses for further research.</p