Search

The SARS-CoV-2 virion responsible for the current world-wide pandemic COVID-19 has a characteristic Spike protein (S) on its surface that embellishes both a prefusion state and fusion state. The prefusion Spike protein (S) is a large trimeric protein where each protomer may be in a so-called Up state or Down state, depending on the configuration of its receptor binding domain (RBD) within its distal, prefusion S1 domain. The Up state is believed to allow binding of the virion to ACE-2 receptors on human epithelial cells, whereas the Down state is believed to be relatively inactive or reduced in its binding behavior. We have performed detailed all-atom, dominant energy landscape mappings for noncovalent interactions (charge, partial charge, and van der Waals) of the SARS-CoV-2 Spike protein in its static prefusion state based on two recent and independent experimental structure publications. We included both interchain interactions and intrachain (domain) interactions in our mappings in order to determine any telling differences (different so-called “glue” points) between residues in the Up and Down state protomers. The S2 proximal, fusion domain demonstrated no appreciable energetic differences between Up and Down protomers, including interchain as well as each protomer’s intrachain, S1-S2 interactions. However, the S1 domain interactions across neighboring protomers, which include the RBD-NTD cross chain interactions, showed significant energetic differences between Up-Down and Down-Down neighboring protomers. This included, for example, a key RBD residue ARG357 in the Up-Down interaction and a three residue sequence ALA520-PRO521-ALA522, associated with a turn structure in the RBD of the Up state protomer, acting as a stabilizing interaction with the NTD of its neighbor protomer. Additionally, our intra chain dominant energy mappings within each protomer, identified a significant “glue” point or possible “latch” for the Down state protomer between the S1 subdomain, SD1, and the RBD domain of the same protomer that was completely missing in the Up state protomer analysis. Ironically, this dominant energetic interaction in the Down state protomer involved the backbone atoms of the same three residue sequence ALA520-PRO521-ALA522 of the RBD with the amino acid R-group of GLN564 in the SD1 domain. Thus, this same three residue sequence acts as a stabilizer of the RBD in the Up conformation through its interactions with its neighboring NTD chain and a kind of latch in the Down state conformation through its interactions with its own SD1 domain. The dominant interaction energy residues identified here are also conserved across reported variations of SARS-CoV-2, as well as the closely related virions SARS-Cov and the bat corona virus RatG13. We conducted preliminary molecular dynamics simulations across 0.1 μ seconds to see if this latch provided structural stability and indeed found that a single point mutation (Q564G) resulted in the latch releasing transforming the protomer from the Down to the Up state conformation. Full trimeric Spike protein studies of the same mutation across all protomers, however, did not exhibit latch release demonstrating the critical importance of interchain interactions across the S1 domain, including RBD-NTD neighboring chain interactions. Therapies aimed at disrupting these noncovalent interactions could be a viable route for the physico-chemical mitigation of this deadly virion.

The cautionary language provided maxims that were directly relevant to how Julius makes sense of his friendships. Julius cannot afford to burn bridges as it is thanks to friendships that he has been able to remain in Japan. Julius was reluctant at first to explain how he got the job that enabled him to legally remain in Japan. Eventually, he admitted that his job resulted from a favour by a “friend of a friend” of his former coach, who also happens to have deep ties to and clout in the distance-running world in Kenya. The creativity of any income must be done individually to get something to sustain their needs. While the definition of the term is open to local interpretations, a common theme relates specifically to development or betterment. Kenyans perceive development to be a state that they are constantly lacking but perpetually desiring, particularly in the context of the deregulation of the economy in 1993.

This collectively written article explores postdigital relationships between science, philosophy, and religion within the continuum of enchantment, disenchantment, and re-enchantment. Contributions are broadly classified within four sections related to academic fields of philosophy, theology, critical theory, and postdigital studies. The article reveals complex and nuanced relationships between various disciplinary perspectives, religions, and political positions, and points towards lot of commonalities between their views to the enchantment, disenchantment, re-enchantment continuum. Some commonly discussed questions include: Where do the mythical, mystical and spiritual end and the rational, objective and empirical begin? How do we find our bearings in the midst of this complexity and where do we search for resources that are trustworthy and reliable? While the article inevitably offers more questions than answers, a common thread between all contributions is the need for an open postdigital dialogue conducted in the spirit of mutual understanding and respect. It is with this conclusion that the article offers a possible route for further development of such dialogue in the future.

Rationale: Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2 (angiotensin-converting enzyme 2), and TMPRSS2 (transmembrane protease serine 2) mediate viral infection of host cells. We reasoned that differences in ACE2 or TMPRSS2 gene expression in sputum cells among patients with asthma may identify subgroups at risk for COVID-19 morbidity.Objectives: To determine the relationship between demographic features and sputum ACE2 and TMPRSS2 gene expression in asthma.Methods: We analyzed gene expression for ACE2 and TMPRSS2, and for ICAM-1 (intercellular adhesion molecule 1) (rhinovirus receptor as a comparator) in sputum cells from 330 participants in SARP-3 (Severe Asthma Research Program-3) and 79 healthy control subjects.Measurements and Main Results: Gene expression of ACE2 was lower than TMPRSS2, and expression levels of both genes were similar in asthma and health. Among patients with asthma, male sex, African American race, and history of diabetes mellitus were associated with higher expression of ACE2 and TMPRSS2. Use of inhaled corticosteroids (ICS) was associated with lower expression of ACE2 and TMPRSS2, but treatment with triamcinolone acetonide did not decrease expression of either gene. These findings differed from those for ICAM-1, where gene expression was increased in asthma and less consistent differences were observed related to sex, race, and use of ICS.Conclusions: Higher expression of ACE2 and TMPRSS2 in males, African Americans, and patients with diabetes mellitus provides rationale for monitoring these asthma subgroups for poor COVID-19 outcomes. The lower expression of ACE2 and TMPRSS2 with ICS use warrants prospective study of ICS use as a predictor of decreased susceptibility to SARS-CoV-2 infection and decreased COVID-19 morbidity.

Background: Hypercalcemia is a relatively common problem that may require hospital admission based on severity. A treatment option for hypercalcemia is calcitonin given intramuscularly or subcutaneously. Purpose: In 2015, calcitonin was on our health system formulary, but due to a sharp rise in cost, restrictions were placed to ensure appropriate utilization. Intervention: These restrictions reserved calcitonin for patients with symptomatic hypercalcemia or severe hypercalcemia, which was defined as an ionized calcium of greater than 1.5 mmol/L and/or total/corrected calcium (Ca) of greater than 13 mg/dL. In addition to providing criteria for its use, calcitonin orders also had an automatic stop date of 24 hours to ensure no more than 2 doses were provided in a 24-hour period. After the initial 24 hours, a patient would have to be reviewed again before any further doses were ordered and administered. If the patient met criteria, an additional 2 doses could be given in the next 24 hours for a total maximum treatment of 4 doses over a 48-hour time frame. Results: An evaluation to assess health system–wide compliance of the usage of calcitonin restrictions regarding utilization, effectiveness, and cost was conducted. In the 2-month study time frame that was examined, there was a decrease in 66 vials of calcitonin that were dispensed. This represents a 43% reduction in usage and an estimated US $450,000 reduction in the total money spent for calcitonin annually. No notable differences in Ca reduction were identified between the groups. Conclusion: This evaluation revealed that putting health system–wide restrictions in use for a high-cost medication can have a major financial impact without compromising clinical efficacy.

Rationale: Cross-sectional studies suggest an exacerbation-prone asthma (EPA) phenotype and the utility of blood eosinophils and plasma IL-6 as predictive biomarkers. Objectives: To prospectively test for EPA phenotype and utility of baseline blood measures of eosinophils and IL-6 as predictive biomarkers. Methods: Three-year asthma exacerbation data were analyzed in 406 adults in the Severe Asthma Research Program-3. Transition models were used to assess uninformed and informed probabilities of exacerbation in year 3. Binomial regression models were used to assess eosinophils and IL-6 as predictive biomarkers. Measurements and Main Results: Eighty-three participants (21%) had ≥1 exacerbation in each year (EPA) and 168 participants (41%) had no exacerbation in any year (exacerbation-resistant asthma). The uninformed probability of an exacerbation in Year 3 was 40%, but the informed probability increased to 63% with an exacerbation in Year 2 and 82% with an exacerbation in Years 1 and 2. The probability of a Year 3 exacerbation with no Year 1 or 2 exacerbations was 13%. Compared with exacerbation-resistant asthma, EPA was characterized by lower FEV(1) and a higher prevalence of obesity, hypertension, and diabetes. High-plasma IL-6 occurred in EPA, and the incident rate ratio for exacerbation increased 10% for each 1-pg/μl increase in baseline IL-6 level. Although high blood eosinophils did not occur in EPA, the incident rate ratio for exacerbations increased 9% for each 100-cell/μl increase in baseline eosinophil number. Conclusions: Longitudinal analysis confirms an EPA phenotype characterized by features of metabolic dysfunction. Blood measures of IL-6, but not eosinophils, were significantly associated with EPA, and IL-6 and eosinophils predicted exacerbations in the sample as a whole.

The SARS-Cov-2 virion responsible for the current world-wide pandemic Covid-19 has a characteristic Spike protein (S) on its surface that embellishes both a prefusion state and fusion state. The prefusion Spike protein (S) is a large trimeric protein where each protomer may be in a so-called Up state or Down state, depending on the configuration of its receptor binding domain (RBD). The Up state is believed to allow binding of the virion to ACE-2 receptors on human epithelial cells, whereas the Down state is believed to be relatively inactive or reduced in its binding behavior. We have performed detailed all-atom, dominant energy landscape mappings for noncovalent interactions (charge, partial charge, and van der Waals) of the SARS-Cov-2 Spike protein in its static prefusion state based on recent structural information. We included both interchain interactions and intrachain (domain) interactions in our mappings in order to determine any telling differences (different so-called “glue” points) between residues in the Up and Down state protomers. In general, the S2 or fusion machinery domain of S is relatively rigid with strong noncovalent interactions facilitated by helical secondary structures, whereas the S1 domain, which contains the RBD and N-terminal domain (NTD), is relatively more flexible and characterized by beta strand structural motifs. The S2 domain demonstrated no appreciable energetic differences between Up and Down protomers, including interchain as well as each protomer’s intrachain, S1-S2 interactions. However, the S1 domain interactions across neighboring protomers, which include the RBD-NTD cross chain interactions, showed significant energetic differences between Up-Down and Down-Down neighboring protomers. Surprisingly, the Up-Down, RBD-NTD interactions were overall stronger and more numerous than the Down-Down cross chain interactions, including the appearance of the three residue sequence ALA520-PRO521-ALA522 associated with a turn structure in the RBD of the Up state protomer. Additionally, our intrachain dominant energy mappings within each protomer, identified a significant “glue” point or possible “latch” for the Down state protomer between the S1 subdomain, SD1, and the RBD domain of the same protomer that was completely missing in the Up state protomer analysis. Ironically, this dominant energetic interaction in the Down state protomer involved the backbone atoms of the same three residue sequence ALA520-PRO521-ALA522 of the RBD with the R-group of GLN564 in the SD1 domain. Thus, this same three residue sequence acts as a stabilizer of the RBD in the Up conformation through its interactions with its neighboring NTD chain and a kind of latch in the Down state conformation through its interactions with its own SD1 domain. The dominant interaction energy residues identified here are also conserved across reported variations of SARS-Cov-2, as well as the closely related virions SARS-Cov and the bat corona virus RatG13. To help verify the potential latch for the Down state protomer, we conducted some preliminary molecular dynamic simulations that effectively turn off this specific latch glue point via a single point mutation of GLN564. Interestingly, the single point mutation lead to the latch releasing in less than a few nanoseconds, but the latch remained fixed in the wild state protomer for up to 0.1 microseconds that were simulated. Many more detailed studies are needed to understand the dynamics of the Up and Down states of the Spike protein, including the stabilizing chain-chain interactions and the mechanisms of transition from Down to Up state protomers. Nonetheless, static dominant energy landscape mappings and preliminary molecular dynamic studies given here may represent a useful starting point for more detailed dynamic analyses and hopefully an improved understanding of the structure-function relationship of this highly complex protein associated with COVID-19.

This article presents 15 autoethnographical texts detailing student experiences at Beijing Normal University in the midst of the Covid-19 pandemic. Contributions have been collected over 6 weeks between 15 February and 1 April 2020, edited by Hejia Wang (assisted by Moses Oladele Ogunniran and Yingying Huang), and supervised by Michael Peters. Through shared in-depth empirical feelings and representations from a wide variety of cultural, historical, and social contexts, the article outlines an answer to the question: How do students, connected virtually but separated physically in an internationalized university, deal with disruption brought about by the Covid-19 pandemic? Student testimonies offer reflections on Covid-19 and Chinese international education, experiences of online teaching and learning, reflections on university coping mechanisms, an account of realities and feelings related to changes in academic life, and discussions on coping strategies in Chinese international higher education. Contributors expose their individual feelings, effects, benefits, challenges, and risk management strategies. Collected at the peak of the Covid-19 pandemic, these testimonies are unable to offer systemic answers to challenges facing the whole world. However, these experiences and feelings will provide important inputs to global discussions about the future of the world, after Covid-19.

This paper analyses and examines Deleuze’s Foucault as a means of investigating intellectual resources for a new sociology – one that, in Foucault’s name, is neither foundationalist nor rep...

The university is a European institution; indeed, it is the European institution par excellence. There are various reasons for this assertion. As a community of teachers and taught, accorded certai...

If suicide is allowed, then everything is allowed. If anything is not allowed, then suicide is not allowed. This throws a light on the nature of ethics, for suicide is, so to speak, the elementary ...

Following involvement in several academic collectively written articles, the authors question traditional notions of the ‘lone’ individualist author model as the expected standard in the humanities as opposed to large research teams in physical sciences. They use Barthes and Foucault to question the function and the concept of the author and assumed notions of subjectivity. Recent collective writing as a form of peer production and publishing is an attempt to reinvent the concepts of authorship, the author subject and author subjectivity. These bring to the fore the processes of peer review, questions of ownership (for example, of what remains in a revision, whose contribution becomes revised and by whom), and blurr the boundaries around author/collective voice and are discussed in this paper. Its transversality is proving as complex as the term suggests, in terms of developing new ways of connecting, thinking, examining and working, in ways that have not been the norm at least in the field of philosophy of education. Contemporary questions of the potential social, philosophical, legal, epistemological and ethical implications for and of authorship and subjectivity have barely been touched on to date, but this article begins to broach this gap.

The next pandemic will erupt, not from the jungle, but from the disease factories of hospitals, refugee camps and cities. Wendy Orent, How Plagues Really Work, https://aeon.co/essays/the-next-pande...

What’s true of all the evils in the world is true of plague as well. It helps men [sic] to rise above themselves.– Albert Camus, The PlagueMany novelists and philosophers have commented on the them...

BackgroundComplex global initiatives, like the Global Polio Eradication Initiative (GPEI), have prevented millions of paralyses and improved the health status of diverse populations. Despite the logistical challenges these initiatives must overcome at several levels, scant methods exist for systematically identifying and reaching a range of actors involved in their implementation. As a result, efforts to document the lessons learned from such initiatives are often incomplete. This paper describes the development and application of the Synthesis and Translation of Research and Innovations from Polio Eradication (STRIPE) systematic approach for identifying a comprehensive sample of actors involved in the GPEI.ResultsThe survey for collecting lessons learned from the GPEI was conducted at the global level and within seven countries that represented GPEI operational contexts. Standard organizational and operational levels, as well as goals of program activities, were defined across contexts. Each survey iteration followed similar methodologies to theorize a target population or “universe” of all polio-related actors in the study area, enumerate a source population of specific individuals within the target population, and administer the survey to individuals within the source population. Based on the systematic approach used to obtain a comprehensive sample for lessons learned in GPEI, steps for obtaining a comprehensive sample for studying complex initiatives can be summarized as follows: (i) State research goal(s); (ii) Describe the program of interest; (iii) Define a sampling universe to meet these criteria; (iv) Estimate the size of the sampling universe; (v) Enumerate a source population within the universe that can be feasibly reached for sampling; (vi) Sample from the source population; and (vii) Reflect on the process to determine strength of inferences drawn.ConclusionsThe application of these methods can inform future evaluations of complex public health initiatives, resulting in better adoption of lessons learned, ultimately improving efficacy and efficiency, and resulting in significant health gains. Their use to administer the STRIPE lessons learned survey reflects experiences related to implementation challenges and strategies used to overcome barriers from actors across an extensive range of organizational, programming, and contextual settings.

The 793nm semiconductor diode cladding pumped Thulium-doped high power fiber laser operates around eye safe 1.9 ~ 2μm and output power can reach to kW level. Those 2μm high power fiber lasers are attractive in various applications in industrial use, medical field, remote sensing and military use. High power, reliable 793nm diodes and cost-effective pump modules are the key component in enabling widespread use of Tm-doped 2μm fiber laser for commercial applications. The latest generation of Coherent AAATM epi design platform is optimized for low internal loss, high quantum efficiency and higher linear power density at 793nm region. Two types of high power diode lasers are tested; one is a single emitter with 100μm emission width and the other is a tailored bar (T-bar) including five 100μm emitters with 1mm pitch. The single emitter can achieve 5.6W output power at 5A with 1.26W/A slope efficiency and 60.3% E/O efficiency. Those single emitters are packaged and coupled into a 100μm fiber. At 5A current, a three single emitter based 100μm fiber-coupled module’s output power is 13.4W and the E/O efficiency is 48.0%. The T-bar can reach up to 30W output power at 30A with 1.19W/A slope efficiency and 56.4% peak E/O efficiency. Nine T-bars are mounted and coupled into a 225μm fiber-coupled module and 150W output power and 47.3% E/O efficiency are achieved at 19.1A current. Both single emitter based and T-bar based fiber-coupled modules show long reliable life; single emitters based module’s life is more than 20,000 h at 4A and T-bars based module’s life is more than 10,000 h at 20A.

In this chapter, the author maintains that Wittgenstein’s work may be given, broadly speaking, a cultural and literary reading which focuses upon his styles. Such a reading legitimates both the importance of Wittgenstein – the person – and the significance of his (auto)biography in a way that analytic philosophers might find hard to accept. There are, at least, three ways, which might demonstrate more robustly the pedagogical styles of his thinking. First, one may seek to investigate historically and (auto)biographically the connections between Wittgenstein’s styles of teaching philosophy, relying on accounts and reminiscences of his former students, and his styles of thinking. Second, one can also investigate historically accounts of his experiences as a primary and secondary school teacher in Austria during the crucial period of 1919 to 1929, and the influences upon his thinking during this period. Third, one can look directly at his writings to observe and document these effects on style.

Declarations of the death knell of postmodernism are now quite commonplace. Indeed, various publications such as those that we utilise below suggest that, if anything, postmodernism is at an end an...

The Enlightenment, often referred to as ‘The Age of Reason’, is sometimes periodised by French historians as the years 1715, the death of Louis XIV, and 1789, the start of the French Revolution. Th...

Ludwig Wittgenstein was a reclusive and enigmatic philosopher, writing his most significant work off campus in remote locations. He also held a chair in the Philosophy Department at Cambridge, and ...

The archive is a cultural institution that creates a framework for the social and collective memory and as such is one of the collection of knowledge institutions that not only preserves and classi...

This speculative paper enquires into the discourse of the ‘end of labour’ or ‘disappearance of labour’ as a result of the development of ‘intelligent capitalism’ clearly seen in ‘intelligent manufa...

Fascism is hostile to egalitarianism and loathes liberalism. It champions ‘might is right’, a Darwinian survival of the nastiest, and detests vulnerability: the sight of weakness brings out the jac...

This paper draws on authors’ recent works on cybernetics, complexity theory, quantum computing, Artificial Intelligence, deep learning, and algorithmic capitalism, and these ideas are brought together to develop a critical philosophy of the postdigital. Quantum computing is based on quantum mechanics and offers a radically different approach from classical comouting based on classical mechanics. Cybernetics, and complexity theory, provide insight into systems that are too complex to predict their future. Artificial Intelligence and deep learning are promising the final stage of automation which is not compatible with the welfare state based on full employment. We have thus arrived into the age of algorithmic capitalism, and its current phase, ‘biologization of digital reason’ is a distinct phenomenon that is at an early emergent form that springs from the application of digital reason to biology and the biologization of digital processes. Rejecting a fully mechanical universe, therefore, a critical pedagogy of the postdigital is closely related to Whitehead’s process philosophy, which is a form of speculative metaphysics that privileges the event and processes over and above substance. A critical philosophy of the postdigital is dialectically interrelated with the theories such as cybernetics and complexity theory, and also processes such as quantum computing, complexity science, and deep learning. These processes constitute the emerging techno-science global system, perpetuate (algorithmic) capitalism, and offer an opportunity for techno-social change.

George Yancy is professor of philosophy at Emory University. He is one of the leading scholars in the US on critical philosophy of race and critical whiteness studies. Yancy received his BA (cum la...

The juridification of Chinese society has gone through four distinct historical phases: an early stage based on Confucian moral law, the introduction of German civil law, followed by socialist (Sov...

Is anyone else here solipsistic, or is it only me?–Posted on a website ‘The Most Intellectual Jokes’Every age and every culture invents its own form of anti-intellectualism.–Apologies to Tolstoy.Se...

Dans « Time and place for Philosophy », Cavell (2008) discute de la « lecture politique » de Wittgenstein (attribuee a Kripke) et illustree par ce qu’il appelle la « scene d’instruction » des Recherches philosophiques (Wittgenstein 2005 : §217) et par « des episodes dans la vie de Wittgenstein qui semblent accrediter une telle lecture ». Cavell fait reference a « l’histoire bien connue de Wittgenstein qui frappe un eleve », dans laquelle le pouvoir est exclusivement du cote de l’enseignant. Wittgenstein a suivi une formation d’enseignant a Vienne en 1919 et a enseigne dans une ecole d’un village rural en Autriche jusqu’en 1926. Il a demissionne brusquement apres l’incident qui l’a implique dans un cas de maltraitance sur un enfant et qui a debouche sur un proces qui s’est tenu a Gloggnitz des le 17 mai 1926, et qui a dure plusieurs mois. Le juge a demande une expertise psychiatrique de Wittgenstein dont le rapport a disparu. « L’incident Haibauer », comme on a fini par l’appeler, constitue un episode central et toujours brulant dans la propre constitution psychologique de Wittgenstein et son evolution ethique — un incident sur lequel il est revenu des annees plus tard comme un des fondements pour sa « confession ». En me distinguant aussi bien de la lecture romantique de la figure de l’enfant par Cavell, que de la philosophie de l’enfant de Matthews (2006), j’adopte une lecture historique de Wittgenstein sur la figure de l’enfant. Ma ligne argumentative tente d’eviter une essentialisation de l’enfant et une forme d’adultocentrisme, en historicisant la subjectivite de l’enfant. Le developpement de l’argumentation entend se centrer sur et explorer l’incident biographique auquel Cavell refere de maniere plus detaillee du fait de la lumiere qu’il jette sur la sensibilite didactique de Wittgenstein et son etat d’esprit (en particulier ses pensees suicidaires) durant la periode ou il a ete instituteur et durant laquelle il a ete en relation avec les enfants autrichiens a qui il enseignait. Cette approche historique a pour effet de mettre en relation autant la didactique que « la discipline » de son enseignement avec le contexte culturel de son epoque, c’est-a-dire l’Autriche des annees 20 en prise avec la reforme educative de Glockel qui introduisait une pedagogie inspiree de principes socio-democrates. Cet article aimerait aussi imaginer ce que pouvait bien contenir de pertinent le rapport psychiatrique suggerant le diagnostique d’un Wittgenstein souffrant, durant son enfance, d’autisme et du syndrome d’Asperger, pour comprendre ses difficultes a apprendre a parler durant sa phase « solipsiste », son combat pour soutenir une vie sociale satisfaisante, et son interet philosophique pour l’acquisition du langage.

The worst readers are those who behave like plundering troops: they take away a few things they can use, dirty and confound the remainder, and revile the whole.–Nietzsche (1879) Human, All Too Huma...