bluuebunny/crossref_metadata_2025 huggingface dataset:
Devices Go Solid State
Authors: Solymar Laszlo
Published: June 2021

This is the story of the birth of the transistor and of the growing understanding of the theory and technology of solid state devices. The transistor was invented at Bell Laboratories by William Shockley, John Bardeen and Walter Brattain. They received the Nobel Prize in 1956.The next advance was putting more and more units on a substrate, initiating the age of integrated circuits. Moore’s Law in its original form states that the number of transistors on a substrate will double every year. As the price of computers using transistors plummeted, the number of computers sold rose fast.
The Communications–Computing Symbiosis: The Beginning
Authors: Solymar Laszlo
Published: June 2021

Chapter 16 discusses the history of the computer. Important events include IBM bringing out the personal computer, and Xerox PARC inventing the graphical user interface. Paul Allen and Bill Gates left Harvard in 1975 to set up a computer laboratory. A year later Steve Jobs and Steve Wozniak set up Apple, followed soon by Dan Bricklin inventing the electronic spreadsheet. At the start of the 1980s Gates leased the MS-DOS operating system to IBM. Prior to all this, in 1969 the Advanced Research Product Agency set up ARPANET, the predecessor of the Internet. Other topics covered in this chapter include the birth of electronic mail, uses and abuses of the Internet, security and coding, and the Minitel in France. The last part of the chapter looks at the Soviet Union and the InterNyet.
The Future
Authors: Solymar Laszlo
Published: June 2021

Some past predictions of the future are discussed, how both in Britain and in France during the nineteenth century illustrated newspapers predicted that by the year 2000 communications between people would involve sending moving pictures from faraway places. A few major technical innovations are envisaged. Most things will just be improved, e.g. full movies will be downloadable in seconds. In the political sphere it is emphasized that apart from a small elite, interest in politics will decline. In most parts of the world people will be happy to accept the word of authorities on any subject. Education will sink to its lowest common denominator.
Unfinished Reform of the Institutions Enforcing UK Competition Law
Authors: Lyons Bruce
Published: June 2021

Chapter 8 on institutional reform written by Bruce Lyons notes that the period since 1998 has seen major changes in competition law, including: public interest was replaced by promotion of competition as the primary duty; anti-competitive agreements and abuse of a dominant position were prohibited, with significant penalties for breach; and the minister withdrew from case decisions, making the institutions determinative. There were also major organizational changes, including merger of the OFT and the Competition Commission to form the Competition and Markets Authority, and establishment of the Competition Appeal Tribunal as a specialist appeals body. In the chapter, Lyons considers the evolution of these institutions from the perspective of how they frame and influence the quality of first instance determinations. Institutions are hostages to their history, and he traces some of the problems faced by the CMA to its institutional roots. New challenges beyond its control are also identified. Reform is needed. The chapter concludes that some of the CMA’s suggestions for legislation are misguided, particularly in replacing its competition duty with ‘the consumer interest’ and reducing the standard of review by the CAT. Alternative proposals are appraised, including a potential change to a prosecutorial system. Lyons argues convincingly that genuinely independent decision-making within the CMA should be preferred and would permit a more limited standard of review.
Poetry and the Language of Oppression
Authors: Bugan Carmen
Published: June 2021

Poetry and the Language of Oppression is an incursion into the creative process that engages with the experience of oppression and the reclamation of freedom in the context of the Cold War. What is freedom in language and how does the poet who has endured political oppression write himself or herself free? What is literary testimony and how does it reflect one’s artistic values? How do we govern ourselves with language? Oppression, repression, expression, as well as their tools (incarceration, surveillance, exile, gestures in language) have been with us in various forms throughout history; the present discussion represents a particular aspect of these conditions of our humanity as they play out in our time, providing another instance of the communion, and sometimes confrontation, with the language that makes us human.
Sounding The Deeps of Nature
Authors: Bugan Carmen
Published: June 2021

The concept of oppression, just like the concept of freedom, has a narrative character: there is a narrative that accompanies every transaction of meaning taking place between all of society and the larger forces of the world. The poem and its readers partake in this narrative as well: one that is initiated by the poem, and developed by each of its readers. This chapter addresses the interface between poetry and politics in language, using the reality of oppression in order to probe deeper into the fundamental concept of freedom. The notion of freedom is discussed in the specific context of Cold War oppression and the poetry of resistance, in order to see how that notion has evolved over time. Poetry is understood as a thinking and a feeling ground on which the language of oppression (suppressive) and lyric language (expressive) come into contact, giving a deeper sense of the human condition.
Writing in Turbulent Times
Authors: Bugan Carmen
Published: June 2021

This chapter investigates whether literature that engages with politics is, or indeed should be, political, and in precisely what sense. It discusses the difference between poetry that is profoundly political—dealing with fundamental moral issues—and simple verse propaganda. It also asks whether freedom is/should be a political concept or if it is something more personal, reaching much deeper into our nature. Looking at several effects of political realities on the artistic process, the chapter argues for the necessity to address the larger, and timeless issues such as suffering, hope, and love, rather than adopting a partisan politics in one’s literary work. In portraying the effects of turbulent politics on individual lives, literature has a unique opportunity to ponder and celebrate our humanity. It can counteract the manipulative language of propaganda, by drawing on the rich resources of a language that, through moments of political upheaval, is able to sustain, if those values which sustain can clearly be articulated.
Conclusion
Authors: Bugan Carmen
Published: June 2021

The concluding remarks bring to the discussion the sense that behind the effort to put feelings into words there is a deeper, spiritual need to connect with language and the world, similar to a prayer arising from language and the world, and returning to them. The language to which we all have a right, and use to explain our lives to ourselves, is given to us both as a gift and a responsibility. For the author, the spiritual relationship with language is essential in establishing that sense that one can speak and write with the hope that one will be heard.
Governmental Self-Restraint and Individual Self-Respect
Authors: Kramer Matthew H.
Published: June 2021

This pivotal chapter presents a novel justificatory foundation for the principle of freedom of expression. It elaborates a Stoical ideal of ethical strength as self-restraint, and it contends that a key element of the realization of that ideal by any system of governance lies in the system’s compliance with the principle of freedom of expression. Through arguments based on some of the ideas in Matthew Kramer’s 2017 book Liberalism with Excellence, the chapter then shows how the compliance with that principle by a system of governance crucially affects the levels of self-respect that are warranted for the members of the society over which the system presides. As a consequence, that compliance is essential for the fulfilment of the system’s paramount responsibility to bring about the political and social and economic conditions under which every member of its society can be warranted in feeling a strong sense of self-respect.
Conclusion: The Principle of Freedom of Expression in Practice
Authors: Kramer Matthew H.
Published: June 2021

This chapter concludes Freedom of Expression as Self-Restraint by probing briefly a few of the knotty procedural issues that attend the efforts by any system of governance to implement the moral principle of freedom of expression (or, rather, to implement some constitutional or statutory guarantee that corresponds more or less closely to that moral principle). Among the issues at which the chapter glances are the scalar character of compliance by systems of governance with the principle of freedom of expression, the legal remedies that are apposite for giving effect to the moral obligations imposed by that principle, the location and stringency of the burden of proof in litigation where communicative liberties are at stake, and the location of the general legal powers to invalidate statutes and other laws. The chapter explains why these issues have been consigned to a fairly brief concluding portion of the book, instead of being treated in depth.
Early History of Archaeology Graphs
Authors: Lyman R. Lee
Published: June 2021

The earliest archaeological spindle graph was published in 1883 by natural historian and avocational archaeologist Charles C. Abbott. Evidence that he obtained the idea from paleontology, which first published spindle graphs in the 1830s and 1840s, is circumstantial at best, and differences in graph styles weigh against such borrowing. Several spindle graphs published in the 1890s and early 1900s by archaeologist William Henry Holmes either depict his views on inevitable progressive evolution—a theory rapidly falling from anthropological favor—or were so speculative as to likely have had little influence on the discipline. During the first couple decades of the twentieth century, physicist/geographer/anthropologist Franz Boas (often referred to as the father of anthropology) published numerous line graphs of quantitative data. He influenced archaeologists Leslie Spier and Manual Gamio who used line graphs to display temporally varying frequencies of artifacts. About the same time, the wife and husband team of Madeleine Kidder and Alfred V. Kidder published several line graphs of relative frequencies of pottery types against stratigraphic provenience, seemingly largely as a result of Madeleine’s influence because Alfred never again published such a graph and instead favored phyletic seriation graphs of a type reminiscent of Sir William Flinders Petrie’s sequence dating graphs from the turn of the century.
Shaping a Concept of Terrorist Acts
Authors: Coady C. A. J.
Published: June 2021

Chapter 1 is concerned with bringing some clarity to the widespread conceptual confusion around what terms like “terrorist,” “terrorist act,” and “terrorism” mean. Without being too rigid about definition, it is important to operate with some agreed definitional clarity in the area. The chapter defends the value of such a definitional enterprise and then provides what it calls a tactical definition of a terrorist act that aims to capture a central core involved in talk about terrorism, and opens discussion of terrorist acts to cogent moral assessment. The author’s definition of a terrorist act is: “A political act, ordinarily committed or inspired by an organized group, in which violence is intentionally directed at non-combatants (or ‘innocents’ in a suitable sense) or their significant property, in order to cause them serious harm.” The rest of the chapter discusses advantages of the definition and criticizes a number of objections to it.
The Cultural Master Narrative of Personal Growth
Authors: Bauer Jack
Published: June 2021

This chapter first examines the enduring, cultural ideal of growth, providing a historical context for the modern transformative self. The chapter then introduces cultural master narratives as story prototypes that a culture cherishes in part because they provide individuals with examples of how to live a good life in that culture. The transformative self has a cultural master narrative in the bildungsroman genre of literature—stories that extol character development, personal growth, and self-actualization as the path to happiness, love, and wisdom. Generally speaking, the bildungsroman protagonist rejects the materialistic values of society’s mainstream and forges a personal path of humane growth. On this path, the protagonist learns how to resolve internal conflicts such as money versus meaning, self-discovery versus self-invention, individuation versus interdependence, and playing roles versus living authentically. The chapter introduces characters from a handful of bildungsroman novels that will serve to illustrate concepts throughout the book.
The Transforming, Transformative Self
Authors: Bauer Jack
Published: June 2021

The developmental path of the transformative self is not straightforward, easy, or uniform. This chapter charts how the transformative self itself develops over time, from the theoretical perspectives of Eriksonian identity development and eudaimonic growth. The chapter provides an overview of how one’s degrees of identity exploration and commitment in a world of others shape one’s development over time. High versus low degrees of exploration and commitment yield four identity statuses or pathways: searchers, traditionalists, pathmakers, and drifters. This chapter surveys recent research and theoretical adjustments on the Eriksonian ideal, notably regarding non-idealized pathways of development. Excerpts from the bildungsroman genre illustrate the internal and interpersonal conflicts of eudaimonic growth that arise along all four pathways, plus non-ideal developments, from the perspectives of male and female characters, and then in the contexts of relationships, work, and religious views.
Stages of Transformative Self-Authorship
Authors: Bauer Jack
Published: June 2021

This chapter focuses on the development of narrative structure. The chapter first summarizes basic principles of structural–developmental theories of self. The stages mark increasing degrees of structural complexity and coherence (i.e., value perspectivity) in one’s narrative identity. At each successive stage, the individual is better able to differentiate and integrate perspectives on the self and others. Coupled with themes of eudaimonic growth, these stages also mark the development of wisdom. The stages of self-authorship are pre-authorship, impulsive, egoist, groupish, independent, constructivist, organismic, dynamic, integrative, and post-integrative. Unlike previous stage models, this model emphasizes stages of transformative self-authorship—that is, how the idea of growth is interpreted at each stage with greater complexity and coherence. The chapter also explains how the person of each stage interprets the thinking of previous stages and more advanced stages.
The Self Beyond the Story
Authors: Bauer Jack
Published: June 2021

This brief chapter, more of a coda, questions the capacity of narrative to fulfill the aims of self-identity and the transformative self. The person who has a transformative self uses their life story to cultivate growth and a good life. But in several ways, a growth story urges the individual to transcend their own story and habitual self-identity. The transformative self’s valuing of experiential growth propels the person toward the experience of being alive and toward experiencing meaningful activities and relationships for themself rather than for the identities that they suggest. The transformative self’s valuing of reflective growth beckons the person ever beyond scriptedness and toward transcendent insights that words ultimately cannot capture. Thus, the transformative self leads the person toward eudaimonic growth both with words and beyond them.
Taking Stock: Hale, Heck, and Wright on Neo-Logicism and Higher-Order Logic
Authors: Wright Crispin
Published: June 2021

Four philosophical concerns about higher-order logic in general and the specific demands placed on it by the neo-logicist project are distinguished. The paper critically reviews recent responses to these concerns by, respectively, the late Bob Hale, Richard Kimberly Heck, and myself. It is argued that these score some successes. The main aim of the paper, however, is to argue that the most serious objection to the applications of higher-order logic required by the neo-logicist project has not been properly understood. The paper concludes by outlining a strategy, prefigured in recent work of Øystein Linnebo, for meeting this objection.
Phosphorylation of NONPHOTOTROPIC HYPOCOTYL3 affects photosensory adaptation during the phototropic response
Authors: Kimura Taro , Haga Ken , Nomura Yuko , Higaki Takumi , Nakagami Hirofumi , Sakai Tatsuya
Published: June 2021

Photosensory adaptation, which can be classified as sensor or effector adaptation, optimizes the light sensing of living organisms by tuning their sensitivity to changing light conditions. During the phototropic response in Arabidopsis (Arabidopsis thaliana), the light-dependent expression controls of blue-light (BL) photoreceptor phototropin 1 (phot1) and its modulator ROOT PHOTOTROPISM2 (RPT2) are known as the molecular mechanisms underlying sensor adaptation. However, little is known about effector adaption in plant phototropism. Here, we show that control of the phosphorylation status of NONPHOTOTROPIC HYPOCOTYL3 (NPH3) leads to effector adaptation in hypocotyl phototropism. We generated unphosphorable and phosphomimetic NPH3 proteins on seven phosphorylation sites in the etiolated seedlings of Arabidopsis. Unphosphorable NPH3 showed a shortening of its retention time in the cytosol and caused an inability to adapt to very low fluence rates of BL (∼10−5 µmol m−2 s−1) during the phototropic response. In contrast, the phosphomimetic NPH3 proteins had a lengthened retention time in the cytosol and could not enable the adaptation to BL at fluence rates of 10−3 µmol m−2 s−1 or more. Our results indicate that the activation level of phot1 and the corresponding phosphorylation level of NPH3 determine the dissociation rate and the reassociation rate of NPH3 on the plasma membrane, respectively. These mechanisms may moderately maintain the active state of phot1 signaling across a broad range of BL intensities and contribute to the photosensory adaptation of phot1 signaling during the phototropic response in hypocotyls.
USE OF VACUUM MATTRESSES CAN REDUCE THE ABSORBED DOSE DURING PEDIATRIC CT
Authors: Masuda Takanori , Funama Yoshinori , Nakaura Takeshi , Sato Tomoyasu , Tahara Masahiro , Takei Yasutaka , Yamashita Yukari , Oku Takayuki , Masuda Shouko , Kiguchi Masao , Awai Kazuo
Published: June 2021

To evaluate and compare the absorbed dose and image quality when applying a commercially produced fixation device (group A) and a vaccum mattress fixation device to pediatric patients (group B). We compared the absorbed dose and image noise between the groups at the phantom and clinical study. For phantom study, the measurement absorbed dose for a real time skin dosimeter was 3.0 mGy at the group A and 1.9 mGy at the group B (p < 0.05). For clinical study, computed tomography dose index product, dose-length and effective radiation dose were significantly lower with the group B compared to the group A, (3.4 mGy, 27.0 mGy-cm, and 2.2 mSv vs 4.4 mGy, and 36.7 mGy-cm, and 3.0 mSv), p < 0.05 for all comparisons. Compared to the commercially produced fixation device, the vaccum mattress fixation device composed of a less absorptive material enabled a reduction in the absorbed dose while maintaining the image quality during pediatric CT examinations.
Ethnic and Religious Discrimination in the Wedding Venue Business: Evidence from Two Field Experiments in Germany and Austria
Authors: Carol Sarah , Kuipers Coco , Koesling Philipp , Kaspers Milan
Published: June 2021

We add to the current debate on ethno-religious discrimination by studying to what extent discrimination in the wedding venue business is based on religious or ethnic grounds. Do the two reinforce each other? Does the explicit mentioning of a non-religious wedding help to reduce ethnic discrimination in a secularized society? We draw on two field experiments in Germany and Austria. We sent 805 valid emails to wedding venues. We randomly varied two traits, the names (Arabic-origin and native-origin) and whether the wedding was religious (Islamic or Free Church) or not. Using linear probability models and ordinary least squares regressions, we predicted the likelihood of receiving a confirmation, the response time from venues, the length, formality, and tone of the emails as well as the prevalence of mistakes in the emails. Our analyses showed that couples with Arabic-origin names, celebrating an Islamic wedding, received significantly fewer confirmations compared to couples with native-origin names. Celebrating a non-religious wedding of couples with Arabic-origin names reduced the disadvantage. The study suggests statistical discrimination based on religiosity that is inferred from Arabic-origin names.
Clinician and staff perspectives on potential disparities introduced by the rapid implementation of telehealth services during COVID-19: a mixed-methods analysis
Authors: Phimphasone-Brady P , Chiao J , Karamsetti L , Sieja A , Johnson R , Macke L , Lum H , Lee R , Farro S , Loeb D , Schifeling C , Huebschmann A G
Published: June 2021

The COVID-19 pandemic has rapidly altered ambulatory health care delivery and may have worsened disparities in health care access. To assess the telehealth implementation experiences of ambulatory personnel in different disciplines and their perspectives on potential telehealth disparities, and to make recommendations for more equitable telehealth delivery. We used a convergent parallel mixed-methods design. Clinic managers from geriatric medicine, internal medicine, and psychiatry e-mailed a survey to clinicians and staff regarding experiences with telehealth care delivery. Quantitative survey responses were analyzed with Fisher’s Exact tests. Qualitative responses were coded thematically. Recommendations were categorized by type of implementation strategy. Quantitative and qualitative findings on telehealth disparities were merged in a joint data display. Respondents (n = 147, 57% response rate) were distributed across three specialties: 66% internal medicine, 19% psychiatry, and 14% geriatric medicine. Prior to 2020, 77% of clinicians had never delivered telehealth services. By Spring 2020, 78% reported conducting more than half of clinic visits by telehealth. Among clinicians, 52% agreed/strongly agreed that rapid telehealth implementation exacerbated access to care disparities to: older adult patients, those with limited internet access, and those needing interpretation services. Staff expressed similar difficulties with telehealth set-up especially for these patients. To improve telehealth equity, clinicians recommended to: (i) change infrastructure; (ii) train and educate stakeholders; and (iii) support clinicians. Clinicians and staff reported specific subpopulations had challenges in accessing telehealth visits. To avoid perpetuating telehealth access disparities, further co-discovery of equitable implementation strategies with patients and clinics are urgently needed.
Health-related quality of life impact of scabies in the Solomon Islands
Authors: Lake Susanna J , Engelman Daniel , Sokana Oliver , Nasi Titus , Boara Dickson , Marks Michael , Whitfeld Margot J , Romani Lucia , Kaldor John M , Steer Andrew C , Carvalho Natalie
Published: June 2021

Background

Scabies causes intense itching and skin lesions. A small number of studies have shown that scabies impacts health-related quality of life (HRQoL), but no studies have been conducted in the Pacific region. We assessed the impact of scabies on HRQoL in a high-prevalence setting using the Children's Dermatology Life Quality Index (CDLQI) and Dermatology Life Quality Index (DLQI). We also assessed the validity of these tools in a Pacific Island population.

Methods

The study was conducted in the Solomon Islands. Participants with and without skin disease were randomly selected. HRQoL indices were scored on a scale of 0–30.

Results

We surveyed 1051 adults (91 with scabies) and 604 children (103 with scabies). Scabies had a small impact on HRQoL, with a median DLQI score of 2 (interquartile range [IQR] 0–6) and a CDLQI score of 2 (IQR 0–4). Scores increased linearly with severity. The greatest impact on QoL was due to itch, sleep disturbance and impacts on education and employment.

Conclusions

Scabies has a small but measurable impact on HRQoL. The DLQI and CDLQI scores were discriminated between the skin-related QoL of patients with scabies and the control group, indicating that these tools are appropriate to measure skin-related QoL in the Solomon Islands.
Political barriers in the ratification of international commercial law conventions
Authors: Hoekstra Johanna
Published: June 2021

This article analyses the ratification of international commercial law conventions. The Convention for the International Sale of Goods (CISG) is almost 40 years old. In 2012, Switzerland proposed to the United Nations Commission on International Trade Law (UNCITRAL) to evaluate the CISG and assess whether there was need for a new convention. While UNCITRAL decided not to pursue this further, the questions that Switzerland raised remain pertinent. This is not just with regard to the legal and commercial need of a new convention but also regarding the political viability of such a project. This article focuses on the latter question. It analyses the main considerations that play a part in the ratification process of international commercial law conventions. It concentrates on agenda setting and the key actors and analyses the main barriers encountered during ratification. While this article is written in the context of the aforementioned proposal, the analysis has broader applicability to the ratification process of international commercial law conventions. The main conclusions highlight the importance of raising the visibility of commercial law conventions through lobbying by key stakeholders, including trade associations, formulating agencies, and businesses. The importance of this article lies in understanding the political barriers in the ratification of international commercial law conventions.
The effect of fruits and vegetables in the elevated plasma homocysteine: experience of using a quantile regression approach.
Authors: Steluti Josiane , Verly Eliseu , Fisberg Regina Mara , Marchioni Dirce Maria Lobo
Published: June 2021

The purpose of this issue is to investigate the effect of folate from fruits and vegetables (FV) intake on plasma homocysteine concentration (tHcy), using a quantile regression (QR) approach that allow us to explore whether and how covariates influence various parts of the conditional distribution of tHcy. The study population, selected from the Health Survey in São Paulo‐Brazil, consisted of 574 individuals who completed a 2×24 hr dietary intake protocol and had a blood sample collected. To remove the effects of the within‐person variation and estimate individual intake, we used the Multiple Source Method (MSM). The QR coefficients were estimated for percentiles from 5th to 95th, and compared with results from multiple linear regression using Ordinary Least Squares models. The tHcy was dependent variable and FV intake was the independent variable, adjusted for age, sex, serum B6 and B12, natural folate (other sources than FV), folic acid, betaine, methionine, MTHFR genetic variants, and an interaction between age and FV intake. The association between tHcy with FV intake was inverse and significant. The QR coefficient at 90th percentile was almost twice at 65th (−1.77 and −1.03 respectively). Using the linear regression, the coefficient was −0.97. The association between FV intake and tHcy is not constant through the percentiles of tHcy and tend to be stronger as the tHcy increases. Research support: FAPESP and CNPq.
Soluble epoxide hydrolase (sEH) deficiency inhibits DSS‐Induced colitis and carcinogenesis in Mice
Authors: Zhang Wanying , Li H , Dong H , Liao J , Hammock B D , Yang G‐Y
Published: June 2021

Targeting sEH exhibits anti‐inflammatory effects via blocking hydrolysis of epoxyeicosatrienoic acids (EETs) to diols. This study aims to determine 1) expression of sEH in ulcerative colitis‐associated dysplasia and adenocarcinoma, 2) role of sEH in colitis‐carcinogenesis in mice and in LPS‐activated macrophages in vitro. Using immunohistochemical approach, 88.9% of dysplasia and 94% of adenocarcinoma displayed intense positivity of sEH and only 39% in colonic epithelia (mainly expressed in focally reactive hyperplastic epithelia). Using DSS‐induced colitis carcinogenesis in mice, compared to wild‐type mice, sEH (−/−) mice exhibited a significantly decreased tumor incidence [65% vs. 32%, p<0.05] and a markedly reduced tumor size (59.62±20.91 mm3 vs. 22.42 ± 11.22 mm3). The inflammatory activity, as measured for extent of ulceration/lymphoplasmacytosis in the colon, was significantly lower in sEH (−/−) mice (44.7 ± 24.9% vs. 20.2 ± 16.2%, p<0.01). qPCR assay demonstrated a significant low level of cytokines/chemokines including MCP‐1, iNOS, VCAM‐1, IL‐1β and TNFα. LPS‐activated macrophages treated with EETs showed a significant reduction of IL‐1β and TNFα. Eicosanoic acid metabolic profiling revealed a significant increase of EETs/DHETs ratio. These results indicate that sEH plays an important role in colitis‐carcinogenesis and could serve as a potential target of inflammation and cancer.
Direct and indirect effects of particulate exposure on the heart.
Authors: Gorr Matthew W , Youtz Dane J , Cormet‐Boyaka Estelle , Wold Loren E
Published: June 2021

The present study was designed to examine the effects of PM2.5 on the heart both directly and indirectly through lung‐mediated effectors. To investigate the direct effects of PM2.5 on the heart, we have previously shown that isolated rat cardiomyocytes cultured either directly with diesel exhaust particulate matter (DEP, 25 μg/ml), or indirectly with media collected from the basal side of fully polarized human bronchial epithelial cells (16HBE14o‐ and Calu‐3) cultured on permeable supports, treated with DEP on the apical side. Both treatments resulted in significant reduction in cardiomyocyte contractility as measured using the IonOptix system. Dysfunction by direct DEP treatment was reversible by pre‐treatment with the antioxidants tiron, N‐acetyl cysteine, apocynin and mito‐tempol. Recent experiments have examined the origins of this dysfunction. We found that mitochondrial‐derived ROS production measured using mitosox red fluorescence was increased in cells treated with DEP. Additionally, direct DEP treatment induced several markers of oxidative stress including Gpx‐6, superoxide dismutase, Nos‐2. Media collected for indirect DEP treatment was examined using a cytokine multiplex assay, and DEP treatment increased the production of IL‐8, IL‐6, MCP‐1 and RANTES.
Deficiency of urokinase plasminogen activator suppresses epithelial sodium channels in tracheal epithelial cells
Authors: JI HONG‐LONG , Chen Zaixing , Liang Xinrong , Zhao Runzhen , Zhao Meimi
Published: June 2021

Epithelial sodium channels (ENaC) govern transepithelial salt and fluid transport in tracheal, bronchi, and lungs. Fibrinolytic proteases play a crucial role in airway and lung injury and repair. We hypothesized that urokinase‐like plasminogen activator (uPA) regulates respiratory ENaC activity in primary mouse tracheal epithelial cells. The short‐circuit currents in confluent monolayer cells were compared between wild type and uPA null mice. Knockout of uPA led to depressed ENaC activity in both intact and permeabilized cells significantly. A significant decrease in Na+/K+‐ATPase activity was observed as well. Application of uPA and plasmin partially restored ENaC activity and increased cleavage of alpha ENaC proteins in confluent monolayers. ERK1/2 but not Akt phosphorylation was augmented in uPA−/− cells and lungs. Taken together, uPA may regulate ENaC activity via multifaceted mechanisms, including proteolytic cleavage of α ENaC proteins, reduction in vectorial Na+ driving force, and upregulation of ERK1/2 phosphorylation.

Supported by NIH HL87017 and HL95435
Paradoxical anaerobism in desert pupfish
Authors: Heuton Matt , Steinberg Spencer , Hillyard Stanley , van Breukelen Frank
Published: June 2021

Pupfish in the genus Cyprinodon migrated into the Mojave Desert when the region contained a network of large lakes and interconnecting streams. Climate change over the past ten thousand years has resulted in isolated populations in remaining warm springs and pools. Devils Hole is such a pool with stable temperatures between 33 and 34° C and a small population of C. diabolis whose population fell to 38 adult fish counted in 2006. Reproduction occurs on a shallow ledge where temperatures range from 26° C in the winter to 39° C in the summer. We hypothesized that the warm temperatures of the pool were detrimental to the fish. We used a refuge population of C. diabolis to measure oxygen consumption (VO2) of fish acclimated to 28 and 33° C. The 28° C acclimated group (Control) showed a consistent pattern of VO2 over a 2–4 hour experimental period. The 33° C acclimated group showed three patterns: 1) Predictable, i.e. like the 28° C group. 2) Variable, fluctuated between depressed VO2 and values near that of the Predictable group. 3) Intermittent, characterized by periods where VO2 virtually ceased for as long as 67 minutes. Fish showing intermittent VO2 were actively ventilating. Fish acclimated to 33° C produced 7.3X more ethanol than fish acclimated to 28° C indicating use of anaerobic metabolism despite the availability of oxygen.
Scaling of midgut perimeter and amino acid transporter expression in Manduca sexta larvae
Authors: Gillen Christopher M. , Itagaki Haruhiko , Yeoh Aaron J. , Vela‐Mendoza Allison V. , Connell Katheryn P. , Sanderlin Allen G. , Kerkhoff Andrew J.
Published: June 2021

Metabolic rate of tobacco hawkmoth (Manduca sexta) larvae increases with body mass to the approximately 0.90 power, greater than the 0.67 and 0.75 scaling exponents predicted by isometric increase of surface area and fractal geometry of exchange networks. We evaluated whether increased midgut folding and/or nutrient transporter expression in larger larvae contribute to this discrepancy. In 3rd through 5th instar larvae, midgut wet mass scaled with an estimated exponent of 0.85. Exponents for anterior, middle, and posterior midgut were 0.96, 0.70 and 0.85, respectively. Composite micrographs of transverse sections revealed progressively increased folding of the midgut perimeter in 1st through 5th instar larvae. These results suggest that relative midgut surface area declines less than predicted by theoretical models as larvae grow. Also, expression of mRNA encoding a potassium amino acid transporter (KAAT1) increased 2 to 3‐fold in 5th instar compared to 4th instar larvae. To assess the consequences of altering the expression of KAAT1, we used RNA interference to decrease midgut KAAT1 expression. Delivery of a 453bp dsRNA encoding KAAT1 through direct injection into the hemolymph resulted in an approximately 6‐fold reduction in KAAT1 mRNA expression, while oral delivery in a sucrose droplet did not reduce KAAT1 expression. Knockdown of KAAT1 mRNA expression did not affect larval growth. (NSF‐DMS0827208)
Type II diabetes increases myocardial mitochondrial DNA (mtDNA) damage by altered mitochondrial topoisomerase function
Authors: Edwards John Grenville , Piteo Brian , Laurent Dimitri , Mitry Maria , Hicks Steven
Published: June 2021

Mitochondrial dysfunction has a significant role in the development of diabetic cardiomyopathy. Using neonatal cardiomyocytes and the Goto‐Kakizaki (GK) rat as models of type II diabetes, we investigated if mitochondrial topoisomerases contributed to mitochondrial dysfunction. In cardiomyocytes elevated glucose significantly decreased ATP production and cytochrome oxidase (COX) activity. Diabetes significantly decreased cytochrome oxidase activity in GK left ventricle (LV). Diabetes significantly increased mtDNA damage, in both glucose‐challenged cardiomyocytes and GK LV. TTGE analysis of COX3 identified nucleotide substitutions in the GK LV mtDNA that altered the primary protein sequence. In isolated mitochondria, diabetes increased DNA cleavage activity and incubation with topoisomerase inhibitors significantly altered this response. Immunoprecipitation with a mtTOP1 antibody partially blocked DNA cleavage. The presence of 60 μM H2O2 increased mitochondrial topoisomerase dependent DNA cleavage: implicating ROS as a modifier of topoisomerase function. Separate from a direct impact of oxidative stress on mtDNA, ROS‐induced alteration of mitochondrial topoisomerase function propagated mtDNA damage. Our findings suggest that mitochondrial topoisomerase dysfunction contributes to the development and complications of diabetic cardiomyopathy. Supported in part by NIH HD065551.
Rapamycin induces diabetes mellitus only in male mice
Authors: Partap Uttara , Swoap Steven J.
Published: June 2021

While rapamycin is known to increase longevity in aging mice, it can also induce insulin resistance. We tested the hypothesis that long‐term rapamycin dosage induces diabetes mellitus in mice. Outbred male and female mice were fed on a rapamycin‐containing diet for approximately 1 year, and analyzed for markers of diabetes. We found that only male mice exhibited diabetic symptoms, including elevated fasting blood glucose (256±12 vs. control: 87±5mg/dL) and detectable urine glucose (14,600±1,680mg/dL). Female mice remained euglycemic (91±3 vs. control: 83±2mg/dL) with no detectable urine glucose. We then hypothesized that an ovarian‐derived hormone was protective against rapamycin‐induced diabetes. A subset of the males and females from the initial group was gonadectomised (cast; ovx). Within two weeks of ovx, fasting blood glucose was significantly elevated as compared to controls (103±5 vs. 70±4mg/dL). Glucose tolerance tests demonstrated that ovx mice became more glucose intolerant as compared to controls (area under the curve analysis 5530±1130min‐mg/dL vs. control: 3250±220min‐mg/dL). No significant difference in fasting blood glucose or glucose tolerance was observed in cast males. Collectively these data indicate that rapamycin can induce diabetes mellitus in mice, and that an ovarian hormone, likely 17‐β estradiol, protects against the progression of rapamycin‐induced diabetes in mice.
Inhibitory neuromuscular transmission in the mouse distal colon is mediated by SK and calcium activated chloride channels
Authors: Bhattarai Yogesh , Galligan James
Published: June 2021

Neurogenic colonic smooth muscle relaxation is caused by inhibitory junction potentials (IJPs). We attempted to identify neurotransmitter, receptor and ion channel mechanisms that mediate IJPs in the mouse distal colon.

Methods

Intracellular recordings were obtained from circular smooth muscle cells in vitro. Electrical field stimulation was used to evoke IJPs. Drugs were applied in the organ bath solution.

Results

The P2Y1 receptor antagonist MRS‐2179 (10 μM) reduced IJP amplitude (66 ± 4%) and area (24 ± 11%). The nitric oxide synthase (NOS) inhibitor L‐NNA (100 μM) reduced IJP area (33 ± 8%) but not amplitude. Co‐application of MRS‐2179 and L‐NNA blocked IJPs. The SK channel blocker, apamin (0.1 μM) reduced IJP amplitude (36 ± 5%) and area 41 ± 12%. The Ca2+‐activated Cl‐channel blocker, niflumic acid (50 μM) reduced IJP amplitude (52 ± 6%) and area (44 ± 6%). Co‐application of niflumic acid and apamin blocked IJPs. ATP (5 mM) produced a larger hyperpolarization (20 ± 2 mV) compared to β‐NAD (10 ± 3 mV). MRS‐2179 and apamin reduced the ATP response amplitude by 34 ± 8% and 31 ± 1% respectively. MRS‐2179 and apamin reduced the β‐NAD (5 mM) response by 71 ± 14% and 61 ± 5% respectively.

Conclusion

IJPs are mediated via P2Y1 and NOS mediated pathways, which involve SK and Ca2+‐activated Cl‐channels. Responses caused by β‐NAD more closely mimic the IJP compared to ATP. Supported by NIH (DK094932).
Detection of local serotonin release and clearance in the human small intestine using amperometry
Authors: France Marion , Galligan James , Swain Greg
Published: June 2021

Serotonin (5‐hydroxytryptamine, 5‐HT) is an important signaling molecule in the gastrointestinal tract where it regulates motility and sensation. Alterations in 5‐HT signaling lead to impaired motility and visceral sensation. 5‐HT released from enterochromaffin (EC) cells residing in the mucosa acts at nearby intrinsic and extrinsic primary afferent neurons and its actions are terminated by uptake by the serotonin re‐uptake transporter (SERT). Continuous amperometry (CA) is used to investigate 5‐HT signaling mechanisms in real time near the mucosal surface (i.e. near sites of release and uptake). In CA, a potential applied to a working electrode will oxidize 5‐HT molecules arriving at the electrode surface at a mass transport limited rate producing a current. A current approach in which the electrode distance in relation to the mucosal surface decreases in a step‐wise fashion, can give information on 5‐HT uptake and release by the slope−1 and intercept slope−1 ratio, respectively, derived from a linear fit of a ln(current) vs. electrode distance plot. Uptake blocked by fluoxetine is indicated by an increase in the slope−1. Measurements have been made in human small intestine obtained from patients undergoing bariatric surgery. Fluoxetine (1 μM) increased the slope−1 in preparations. Preliminary results suggest that this current approach is suitable for measurements in human small intestine and fluoxetine can be used to study SERT function.
Disruption of Shp2 tyrosine phosphatase promotes Hes1/Stat3 complex in intestinal epithelia, contributing to enhanced self‐renewal capacity and impaired differentiation in the crypt niche
Authors: Gui Qiu , Zhang Xue , Xu Lin , Cheng Hongqiang , Ke Yuehai
Published: June 2021

Self‐renewal program enables stem cells to be maintained throughout a lifetime, and to retain the capacity to produce the desired functional cells. However, the molecular mechanisms regulating self‐renewal and differentiation remain unclear. We previously reported that Src‐homology 2 domain‐containing phosphatase 2 (Shp2) is essential for stem cell activity; however, its roles in tissue‐specific stem cells remain largely controversial. Here, we aimed to dissect the in vivo role of Shp2 in intestinal stem cells using a genetic approach. Mice with intestinal‐specific Shp2‐deficiency presented growth retardation with dysfunctional lipid absorption and glucose homeostasis, and postnatal lethality at the age of 6–8 weeks. Moreover, an incomplete crypt‐villus axis, with self‐renewal expansion and reduced epithelial differentiation was observed in 4‐week‐old Shp2‐deficient mice. Mechanistically, intestinal epithelium‐specific deletion of Shp2 activated both Notch and JAK/Stat signaling pathways, which fulfill overlapping roles in growth and differentiation regulation by facilitating Hes1/Stat3 complex formation in intestinal epithelia, so contributing to a weakened differentiation capacity in the crypt niche. Furthermore, we found that Shp2 repressed Hes1 and Stat3 interaction, which coordinates cross‐talk between the Notch and JAK/Stat pathways in Lgr5+ cells. Lgr5 expression is enhanced in Shp2‐deficient mice, while the number of BrdU+ cells also increased. Together, these observations provide the first evidence that Shp2 regulates self‐renewal of intestinal stem cells and their functional differentiation.
Effects of different sweeteners on incretin hormone secretion, gastric emptying, intragastric distribution and postprandial glycemia in healthy humans
Authors: Pereira Ricardo Motta , Secaf Marie , de Oliveira Ricardo Brandt
Published: June 2021

The global rises in the prevalence of obesity and diabetes mellitus led to an increase of sweeteners consumption. Peptides called incretins, such as glucagon‐like peptide 1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) are able to regulate appetite, blood glucose (BG) and gastric emptying (GE) whereas the effects of sweeteners on this release are not well established.

Objective

Determine the effects of addition of sucrose, sorbitol, sucralose or stevia on a standard liquid test meal, on GE and intragastric distribution (ID), as well as on BG, plasma insulin, GIP and GLP‐1 in humans.

Design

Ten male healthy volunteers were studied on 4 separate occasions. Fifteen grams of each substance was added to the test meal one each occasion. GE and ID were determined by scintigraphy, BG, plasma insulin and incretins were determined at fasting until 120 min after the meal ingestion by a glucometer and specifics immunoassay kits.

Results and conclusions

GE and ID are not different among meals prepared with sucrose or sweeteners. The addition of sucrose or stevia caused significant increases of BG. The addition of sucrose, sucralose and stevia caused significant increases of insulin. Plasma GLP‐1 was similarly increased after all meals eaten. Sucrose or sucralose led to increase of GIP concentration relative to fasting. This can explain the increase in plasma insulin after ingestion of test meal added sucralose.
Increased oxidative stress with reduced responsiveness of circulating leukocytes following pulmonary metal‐rich particulate matter exposure
Authors: Antonini James Michael , Zeidler‐Erdely Patti C , Young Shih‐Houng , Hulderman Tracy , Kashon Michael L , Gu Ja K , Salmen‐Muniz Rebecca , Meighan Terence G , Roberts Jenny R , Erdely Aaron
Published: June 2021

Pulmonary exposure to metal‐rich particulate matter (PM) generated from welding causes localized immunosuppression. The aim of this study was to evaluate the molecular changes and responsiveness of circulating leukocytes following exposure. Rats were exposed to manual metal arc stainless steel welding fume (MMAW‐SS) at 2 mg/rat by intratracheal instillation and sacrificed at 4 and 24 hr post‐exposure. Collected whole blood was then challenged with and without LPS for 24 hr. After incubation, supernatants were collected for protein analysis and the cellular fraction was collected for global gene expression changes. Also, mononuclear cells were isolated and analyzed for oxidative stress by flow cytometry and confocal microscopy. Ex vivo leukocyte stimulation with LPS showed reduced production of CCL4, CXCL2, CXCL10 and TNF‐alpha protein in MMAW‐SS treated rats. Interestingly, cellular gene expression changes from MMAW‐SS and PBS rats were similar indicating effects were not related to transcription. Since oxidative stress can affect translation, isolated mononuclear cells were tested and showed increased basal levels of oxidative stress. These results showed increased oxidative stress with a reduced responsiveness of circulating leukocytes providing mechanistic insight into epidemiological and experimental evidence illustrating immunosuppression following a metal‐rich PM exposure.