More than twenty years ago, a biological regulation of climate was proposed whereby emissions of dimethyl sulphide from oceanic phytoplankton resulted in the formation of aerosol particles that acted ...as cloud condensation nuclei in the marine boundary layer. In this hypothesis--referred to as CLAW--the increase in cloud condensation nuclei led to an increase in cloud albedo with the resulting changes in temperature and radiation initiating a climate feedback altering dimethyl sulphide emissions from phytoplankton. Over the past two decades, observations in the marine boundary layer, laboratory studies and modelling efforts have been conducted seeking evidence for the CLAW hypothesis. The results indicate that a dimethyl sulphide biological control over cloud condensation nuclei probably does not exist and that sources of these nuclei to the marine boundary layer and the response of clouds to changes in aerosol are much more complex than was recognized twenty years ago. These results indicate that it is time to retire the CLAW hypothesis.
The generation of insulin-producing pancreatic β cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation therapy in diabetes. However, ...insulin-producing cells previously generated from human pluripotent stem cells (hPSC) lack many functional characteristics of bona fide β cells. Here, we report a scalable differentiation protocol that can generate hundreds of millions of glucose-responsive β cells from hPSC in vitro. These stem-cell-derived β cells (SC-β) express markers found in mature β cells, flux Ca2+ in response to glucose, package insulin into secretory granules, and secrete quantities of insulin comparable to adult β cells in response to multiple sequential glucose challenges in vitro. Furthermore, these cells secrete human insulin into the serum of mice shortly after transplantation in a glucose-regulated manner, and transplantation of these cells ameliorates hyperglycemia in diabetic mice.
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•Stem-cell-derived β (SC-β) cells secrete insulin upon glucose stimulation in vitro•SC-β cells resemble human islet β cells by gene expression and ultrastructure•SC-β cell transplantation ameliorates hyperglycemia in mice•SC-β cells provide a platform for therapeutic development and disease modeling
Functional pancreatic β cells are generated from human pluripotent stem cells using a scalable, in vitro differentiation protocol. This Resource provides a valuable platform for therapeutic development and disease modeling in diabetes.
Optical microscopic imaging offers opportunities to perform noninvasive assessments of numerous parameters associated with the biochemistry, morphology, and functional state of biological samples. ...For example, it is possible to detect the endogenous fluorescence from a small number of important biomolecules, including NADH and FAD, which are two coenzymes involved in key metabolic pathways such as glycolysis, the Krebs cycle, and oxidative phosphorylation. Here, we review different imaging approaches to isolate the fluorescence from these chromophores in two- and three-dimensional samples and discuss the origins and potential interpretation of the observed signals in terms of cell metabolic status. Finally, we discuss the challenges and limitations of these approaches, as well as important research directions that we expect will evolve in the near future.
Our title alludes to the three Christmas ghosts encountered by Ebenezer Scrooge in A Christmas Carol, who guide Ebenezer through the past, present, and future of Christmas holiday events. Similarly, ...our article takes readers through a journey of the past, present, and future of medical AI. In doing so, we focus on the crux of modern machine learning: the reliance on powerful but intrinsically opaque models. When applied to the healthcare domain, these models fail to meet the needs for transparency that their clinician and patient end-users require. We review the implications of this failure, and argue that opaque models (1) lack quality assurance, (2) fail to elicit trust, and (3) restrict physician-patient dialogue. We then discuss how upholding transparency in all aspects of model design and model validation can help ensure the reliability and success of medical AI.
•Modern machine learning relies on powerful but intrinsically opaque models.•When applied to the healthcare domain, these models fail to meet the needs for transparency.•We review how opaque models lack quality assurance, fail to elicit trust, and restrict physician-patient dialogue.•We then discuss how transparency in model design and validation can help ensure the reliability of medical AI.
The search for axions has gained ground in recent years, with laboratory searches for cold dark matter (CDM) axions, relativistic solar axions, and ultra-light axions as the subject of extensive ...literature. In particular, the interest in axions as CDM candidates has been motivated by their potential to account for all of the inferred values of in the standard model. Indeed, the value of could be provided by a light axion. We investigate the possibility of complementing existing axion search experiments with radio telescope observations in an attempt to detect axion conversion in astrophysical magnetic fields. Searching for a CDM axion signal from a large-scale astrophysical environment provides new challenges, with the magnetic field structure playing a crucial role in both the rate of interaction and the properties of the observed photon. However, with a predicted frequency in the radio band (200 MHz-200 GHz) and a distinguishable spectral profile, next-generation radio telescopes may offer new opportunities for detection. The SKA-mid telescope has a planned frequency range of 0.4-13.8 GHz with optimal sensitivity in the range of ∼2-7 GHz. Considering observations at ∼500 MHz, the limiting sensitivity is expected to be ∼0.04 mK based on a 24 hr integration time. This compares with a predicted CDM axion all-sky signal temperature of ∼0.04 mK using SKA Phase 1 telescopes and up to ∼1.17 mK using a collecting area of (1 km)2 as planned for Phase 2.
Type 1 Diabetes (T1D) therapies have focused on restoring beta cell function via exogenous insulin or islet transplant. While promising, these approaches fail to account for the role of alpha cells ...and intra-islet communication in disease etiology. Alpha cells secrete glucagon and maintain effective paracrine signaling with beta cells to maintain glucose homeostasis and metabolic control. Mounting evidences suggest that impaired alpha cell function is a significant contributor to disease progression. Understanding triggers of alpha cell dysfunction and the resulting effects will be crucial for restoring both beta and alpha cell function in T1D. Lack of human alpha cell models have limited progress towards this goal. We recently reported a protocol to generate human alpha cells from stem cell sources (SC-alpha). Using these SC-alpha cells, we have established a T1D disease model to identify the triggers that induce alpha cell dysfunction. Importantly, we have identified defects in proglucagon processing that mimic those observed in diabetes and have identified conditions that modulate proglucagon processing and secretion. Here we demonstrate that exposure of SC-alpha cells to diabetogenic stressors such as hyperglycemia, hyperlipidemia, and ER stress impacts the processing of proglucagon and ultimately results in alpha cell dysfunction. We show that upon exposure to these stressors, SC-alpha cells secrete elevated glucagon compared to the control conditions and show a loss of glucose responsiveness. We also observed changes in the secretion of alternate proglucagon processing products, GLP-1, GLP-2, and glicentin. Interestingly, glicentin levels were affected by ER stress induction, but were unaffected by other stressors, suggesting that ER stress plays a direct role in the disruption of proglucagon processing, leading to alpha cell dysfunction. Identifying triggers of alpha cell dysfunction and assessing impacts in proglucagon processing will be a step towards restoring islet paracrine signaling.
Disclosure
S. Shrestha: None. Q. P. Peterson: None.
International trade directly influences US presidential elections. We explore the electoral implications of the increasing tradability of services and the large US surplus in services trade. Our ...paper builds on prior work showing that job insecurity from import competition in manufacturing diminishes political support for incumbents. We construct novel measures of the tradability of an industry using establishment-level data covering nearly all US economic activity. We find increases in incumbent party vote shares in counties with large numbers of workers in high-skilled tradable services as well as goods, and decreases in counties with high employment in low-skilled manufacturing. Incumbent parties are particularly vulnerable to losing votes in swing states with many low-skilled manufacturing workers. In national-level models, we show for the first time that increasing imports (exports) are associated with decreasing (increasing) presidential incumbent vote shares. The national-level effects are large and politically consequential. We also find an Electoral College incentive to protect the manufacturing sector and to oppose trade agreements.
Abstract Purpose Research demonstrates a negative psychosocial impact of infertility among otherwise healthy adults, and distress among adolescents facing the prospect of future infertility due to ...various medical conditions and treatments that impair reproductive health. Guidelines state that providers should counsel transgender youth about potential infertility and fertility preservation (FP) options prior to initiation of hormone therapy. The purpose of this study was to examine the rates of fertility counseling and utilization of FP among a cohort of adolescents with gender dysphoria seen at a large gender clinic. Methods An Institutional Review Board–approved retrospective review of electronic medical records was conducted of all patients with ICD-9/10 codes for gender dysphoria referred to Pediatric Endocrinology for hormone therapy (puberty suppression and/or cross-sex hormones) from January 2014 to August 2016. Results Seventy-eight patients met inclusion criteria. Five children were prepubertal, no hormone therapy was considered, and they were therefore excluded. Of the remaining 73 patients, 72 had documented fertility counseling prior to initiation of hormone therapy and 2 subjects attempted FP; 45% of subjects mentioned a desire or plan to adopt, and 21% said they had never wanted to have children. Conclusions Utilization rates of FP are low among transgender adolescents. More research is needed to understand parenthood goals among transgender youth at different ages and developmental stages and to explore the impact of gender dysphoria on decision-making about FP and parenthood. Discussions about infertility risk, FP, and other family building options should be prioritized in this vulnerable adolescent population.
Honesty and Discretion White, P. Quinn
Philosophy & public affairs,
Winter 2022, 2022-01-00, 20220101, Volume:
50, Issue:
1
Journal Article
Peer reviewed
About what should we be truthful? And why? Disagreement over these questions is foundational, serving as a major point of distinction between rival ethical views. Often overlooked, however, is the ...remarkable consensus between writers as different as St. Augustine, Kant, and Sidgwick. Virtually all parties to the debate have shared two fundamental presuppositions, the first about explanada, and the second about method.
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