The transactivation response‐DNA binding protein of 43 kDa (TDP‐43) is an aggregation‐prone nucleic acid‐binding protein linked to the etiology of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). These conditions feature the accumulation of insoluble TDP‐43 aggregates in the neuronal cytoplasm that lead to cell death. The dynamics between cytoplasmic and nuclear TDP‐43 are altered in the disease state where TDP‐43 mislocalizes to the cytoplasm, disrupting Nuclear Pore Complexes (NPCs), and ultimately forming large fibrils stabilized by the C‐terminal prion‐like (...) domain. Here, we review three emerging and poorly understood aspects of TDP‐43 biology linked to its aggregation. First, how post‐translational modifications in the proximity of TDP‐43 N‐terminal domain (NTD) promote aggregation. Second, how TDP‐43 engages FG‐nucleoporins in the NPC, disrupting the pore permeability and function. Third, how the importin α/β heterodimer prevents TDP‐43 aggregation, serving both as a nuclear import transporter and a cytoplasmic chaperone. (shrink)

This article examines the implications of the transition to online or blended learning for first generation scholars (FGS) brought about by Covid-19. We present the findings of a mixed methods project that draws data from both in-depth qualitative interviews and a large quantitative survey of students at Durham University. We offer a comparative analysis of how FGS contrast to the general student body in relation to a range of key challenges that Covid-19 and the consequent ‘online pivot’ posed to university (...) life including technological, social and resource based issues. Our findings demonstrate that FGS were particularly affected by this shift to online or blended learning. The final substantive section discusses a range of potential mitigation strategies adopted by the School of Government and International Affairs, Durham University, with the assumption that some, at least, of these, and our data, will be of wider relevance in the sector. (shrink)

Detection of Alzheimer’s disease in an early stage is receiving increasing attention for a number of reasons, such as the failure of drug trials in more advanced disease stages, the demographic evolution, the financial impact of AD, and the approval of amyloid tracers for clinical use. Five focus group interviews with stakeholders were conducted.. The verbatim transcripts were analysed via the Nvivo 11 software. Most stakeholder groups wanted to know their own amyloid PET scan result. However, differences occurred between FGs: (...) two groups wanted to know, whilst in the three other groups FG members opted not to know or were still in doubt about their decision. Stakeholders provided insight into their reasons for wanting to know their amyloid PET scan result, for not wanting to know their result, or why they were in doubt about their decision. Several advantages and disadvantages were mentioned as part of knowing their amyloid PET scan result. Certain considerations were clustered in a grey zone, in between advantage and disadvantage, such as the emotional consequences. Clinicians, researchers, and policymakers ought to be aware of the diversity of reasons for wanting to know their result and how possible benefits and risks can be viewed differently. The current findings are of importance for future early diagnosis and disclosure of results in the research setting. (shrink)

Hempel‘s paradox of the ravens, and his take on it, are meant to be understood as being restricted to situations where we have no additional background information. According to him, in the absence of any such information, observations of FGs confirm the hypothesis that all Fs are G. In this paper I argue against this principle by way of considering two other paradoxes of confirmation, Goodman‘s 'grue‘ paradox and the 'tacking‘ (or 'irrelevant conjunct‘) paradox. What these paradoxes reveal, I argue, (...) is that a presumption of causal realism is required to ground any confirmation; but once we grant causal realism, we have no reason to accept the central principles giving rise to the paradoxes. (shrink)

The minimal God exemplifies essential omnipotence, omniscience, and moral perfection, but none of the other properties of the traditional God. I examine the consequences of the minimal God in augmented S5, S4, and Kρσ. The metaphysical consequences for the minimal God in S5 include the impossibility that God—or any other object—might acquire, lose, or exchange an essential property. It is impossible that an essentially divine being might become essentially human, for instance. The epistemological consequences include the impossibility of agnosticism—it is (...) impossible that P(◻︎FG |E) = P(~◻︎FG| E). Indeed, every weaker forms of agnosticism are also impossible—it is impossible that P(◻︎FG |E) = n, n(0 < n < 1). The metaphysical and epistemological consequences for the minimal God in S4 are equally untenable. I show that we can avoid all of these unwelcome epistemological consequences for the minimal God in Kρσ. But Kρσ has some extraordinary metaphysical consequences for the minimal God. All of the problems for the minimal God generalize to the maximal God. (shrink)

In the present note we make use of some information given in [2]. Also, the terminology and notation do not dier from those accepted in [2]; in particular this concerns the formalism for the predicate calculus. Let A be a model of a rst-order language L. We say that A realizes a set of formulas Fla i A j= [a] for some valuation a in A and all 2 . We say that A omits i A does not realize . (...) A formula 2 Fla is consistent with a theory T in i there is a model of T which realizes fg. (shrink)

Numerous studies have investigated the neuro-cognitive mechanism of learning words in isolation or in semantic contexts recently. However, emotion as an important influencing factor on novel word learning has not been fully considered in the previous studies and how emotion affect word learning and the underlying neural mechanism have not been systematically investigated. 16 participants were trained to learn novel concrete or abstract words under negative, neutral and positive contextual emotions in continuous three days, and fufilled the testing tasks in (...) day1 and day3 during fMRI scanning. We compared the brain activations in day1 and day3 aming to investigate the role of contextual emotions in learning different types of words and the corresponding neural plasticity changes. Behaviorally, the performance for the words learned in negative context was lower than the neutral and positive contexts, which indicated that the contextual emotions had significant impact on novel word learning. Correspondingly, the functional plasticity changes of the right angular (AG), bilateral insula and anterior cingulate gyrus (ACC) induced by word learning were modulated by the contextual emotions. And the insula also was sensitive to the concreteness of the learned words. More importantly, the functional plasticity changes of left inferior frontal gyrus(L IFG) and left fusiform(L FG) were interactively influenced by the contextual emotions and words’ concreteness, suggesting that the contextual emotional information had a discriminable effect on different types of words in the neural mechanism level. These results demonstrate that the emotional information in contexts is inevitable for word learning, and the role of contextual emotions in brain plasticity for learning was discussed. (shrink)

First-generation students are more likely to feel misplaced and struggle at university than students with university-educated parents. We assumed that the shutdowns during the Coronavirus-pandemic would particularly threaten FGS due to obstructed coping mechanisms. Specifically, FGS may show lower identification with the academic setting and lower perceived fairness of the university system. We investigated whether FGS and CGS used different defenses to cope with the shutdown threat in a large sample of German-speaking students. Using Structural Equation Modeling, we found that (...) for all students, independent of academic parental background, high levels of system justification were associated with perceiving the learning situation as less threatening, better coping with failure, and less helplessness. However, in comparison to CGS, FGS showed small but significant reductions in system justification and relied more on concrete personal relationships with other students as well as their academic identity to cope with the threatening situation. We discuss implications for helping FGS succeed at university. (shrink)

Transport through the nuclear pore complex (NPC), a keystone of the eukaryotic building plan, is known to involve a large channel and an abundance of phenylalanine–glycine (FG) protein domains serving as binding sites for soluble nuclear transport receptors and their cargo complexes. However, the conformation of the FG domains in vivo, their arrangement in relation to the transport channel and their function(s) in transport are still vividly debated. Here, we revisit a number of representative transport models—specifically Brownian affinity gating, selective (...) phase gating, reversible FG domain collapse, and reduction of dimensionality (ROD)—in the light of new data obtained by optical single transporter recording, optical superresolution microscopy, artificial nanopores, and many other techniques. The analysis suggests that a properly adapted, simplified version of the ROD model accounts well for the available data. This has implications for nucleocytoplasmic transport in general. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Nina Pelikan Straus RETHINKING FEMINIST HUMANISM Important challenges to feminist philosophy have been launched by Martha Nussbaum and Carol Gilligan. Taken together, Nussbaum 's TL· Fragility of Goodness: Luck and Ethics in Greek Tragedy and Phüosophy (1986)1 and Gilligan's In a Different Voice (1982)2 direct us to die consequences of feminism's critique of humanism, supplemented recendy by attempts at a union with Foucaultian genealogy.3 Each of these texts provokes (...) questions about the reliance on deconstructive theories, like those of Michel Foucault, in contemporary feminist discourse. In this essay I will indicate some of the limitations ofthat union and contrast it to the expanding possibilities generated for feminist thought by a revised discourse of modern humanism. The desirability of this revision will appear more clearly once we take up the quarrel ofsome feminists with the humanist tradition and realize that there is no satisfactory single account of what humanism means. Nussbaum's revision of humanism, for example, is based on a reexamination of human cognition, one which includes emotional responsiveness, traditionally associated with women, as a source of ethical knowledge. Gilligan's humanist revision suggests another variety of humanism, grounded in the claim that Freudian psychology's descriptions of the cognitive developments of men and women fail to account for the different approaches to ethical dilemmas expressed by women's voices. Nussbaum's humanism has classical roots in Plato, Aristode, and die Greek tragedies, while Gilligan's humanism is derived from modern psychoanalysis. Such differences in themselves illustrate humanism's long and pluralistic history. Although Nussbaum does not describe herself as a modern feminist and Gilligan does, each of their texts Philosophy and Literature, © 1990, 14: 284-303 Nina Pelikan Straus285 suggests how, respectively, a woman scholar's response to classical Greek tragedy and philosophy and a woman psychologist's approach to psychoanalysis offer reinterpretations of both feminism and humanism. Parallels between Nussbaum's and Gilligan's contributions to philosophy and psychology suggestan innovative study ofvoices, stories, and images which employ woman as a vehicle for a new approach to etiiics.4 Read togedier, they indicate ways that feminists can redescribe the humanist tradition without either succumbing to the essentialist doctrine which Foucault exposes as oppressive in its consequences for women, or by being seduced by Foucault's antihumanism itself. Nussbaum and Gilligan both expose what Annette Baier calls "a striking feature ofmodern moralphilosophizing"—namely, its "avoidance of the concept of love"5—and each suggests how that feature can be transformed. As linked meditations on unsolved problems of our own way of life, Nussbaum's project is to correct the "notoriously crude and hasty" Aristotelian "investigation of the potential of women for excellence " (FG, p. 471), while Gilligan's work is a response to the dire consequences of Freud's influential notion that "women's experience of sexuality and relationships" is a "dark continent."6 One outcome of feminism's use of Foucault's critique of humanism is the possibilityofits settling into a new orthodoxy or politically "correct" position used to measure degrees of feminist commitment. A better outcome is that feminist discourses which have assimilated Foucault's analysis of power may help to combat this threat.7 The threat is taken to be orthodoxy, and Foucault's discourse is characterized as a guarantee against orthodoxy's temptations. A more problematic consequence of die Foucaultian influence, however, is a devaluation of liberal feminist discourses about "human nature" in favor ofthose which follow Foucault by (in Foucault's words) changing the subject and asking instead, "How has the concept of human nature functioned in our society?"8 This change in emphasis depends upon a description of knowledge as inseparable from power—with Foucault's own texts as the most powerful examples of the emphasis. Michel Foucault thus becomes the Strong Poet whom some feminists incorporate or resist in their writings.9 This incorporation can circumscribe their approaches to feminist problems in ways that suggest traditional female bondages to founding-father texts from which Foucaultian discourse is supposed to liberate them. 286Philosophy and Literature The problem is then one oftemptation. Exercising power is pleasurable, and if we stop with the pleasure that assimilating Foucault yields, we... (shrink)

It is usually supposed that the ‘fundamental’ laws of nature must be general, i.e. must essentially begin with a universal quantifier. Other ‘derivative’ laws may not satisfy this requirement but only because they are the logical or mathematical consequences of a set of fundamental laws. As it stands, this requirement is either too strong or trivial. Consider the Newtonian gravitational law: where FG is the impressed gravitational force on x due to y at t, ms is the mass of x, (...) d is the displacement of the center of mass of x from the center of mass of y at t, and G is the universal gravitational constant.. What is the role of the constant “G”? Reflection shows that it is actually a disguised existential quantifier, or, more precisely, a Skolem function replacement for one. Rendering Newtonian mechanics in a parsimonious language, we could drop the “G” and rewrite as The constant “G” could then be defined, if desired, as the unique r satisfying ). Such a theory would have exactly the same deductive consequences as. But has an initial existential quantifier essentially. (shrink)

It is commonplace to view the rigor of the mathematics in Euclid's Elements in the way an experienced teacher views the work of an earnest beginner: respectable relative to an early stage of development, but ultimately flawed. Given the close connection in content between Euclid's Elements and high-school geometry classes, this is understandable. Euclid, it seems, never realized what everyone who moves beyond elementary geometry into more advanced mathematics is now customarily taught: a fully rigorous proof cannot rely on geometric (...) intuition. In his arguments he seems to call illicitly upon our understanding of how objects like triangles and circles behave rather than grounding everything rigorously in axioms.Though widespread, the attitude is in a historical sense puzzling. For over two millenia, mathematicians of all levels studied the arguments in Elements and found nothing substantial missing. The book, on the contrary, represented the limit of mathematical explicitness. It served as the paradigm for careful and exact reasoning. How it could enjoy this reputation for so long is mysterious if careful and exact reasoning demands that all inferences be grounded in a modern axiomatic theory in the way Hilbert did in his famous Foundations of Geometry. By these standards, Euclid's work is deeply flawed. The holes in his arguments are not minor and excusable, but massive and cryptic.With his book Euclid and His Twentieth Century Rivals, Nathaniel Miller makes substantial progress in clearing this mystery up. The book is an explication of FG , a formal system of proof developed by Miller which reconstructs Euclid's deductions as essentially diagrammatic. The holes in Euclid's arguments are taken to appear precisely at those steps which are unintelligible without an accompanying geometric diagram. Interpreting the reasoning in the Elements in terms of a modern axiomatization , …. (shrink)

AimPatients with high myopia reportedly exhibit changes in functional brain activity, but the mechanism underlying such changes is unclear. This study was conducted to observe differences in dynamic spontaneous brain activity between patients with HM and healthy controls via dynamic regional homogeneity analysis.MethodsResting-state functional magnetic resonance imaging scans were performed on 82 patients with HM and 59 HCs who were closely matched for age, sex, and weight. The dReHo approach was used to assess local dynamic activity in the human brain. (...) The association between mean dReHo signal values and clinical symptoms in distinct brain areas in patients with HM was determined via correlation analysis.ResultsIn the left fusiform gyrus, right inferior temporal gyrus, right Rolandic operculum, right postcentral gyrus, and right precentral gyrus, dReHo values were significantly greater in patients with HM than in HCs.ConclusionPatients with HM have distinct functional changes in various brain regions that mainly include the L-FG, R-ITG, R-ROL, R-PoCG, and R-PreCG. These findings constitute important evidence for the roles of brain networks in the pathophysiological mechanisms of HM and may aid in the diagnosis of HM. (shrink)

This article is an inquiry into the discourse phenomenon of grounding, viz. the foreground-background structure. It explains the place of the phenomenon in the structure of discourse and provides evidence of grounding from short news items. Focusing on the surface structure level of discourse organization, the article examines variant marking of the FG-BG articulation at sentence-initial position. Using English and Arabic news data, the article explicates the grounding-signalling function of entities that appear in that position and shows that Arabic news (...) texts rely on certain prefatory expressions to signal the grounding values of underlying propositions. The study underscores the influence of the cognitive level of information on grounding and its marking in the hierarchical structure of discourse. (shrink)

Let AC be a ray coming from the medium DC into the medium CE, and let the density of the former to the latter be as d to e. It is asked, how should the ray ACB be directed so that it is the easiest path of all, or that (AC x d) + (CB x e) is a minimum. Let DC = l, and EC = m. It is given also that FG = f, and let AD = FC (...) = x, CG = EB = f – x. Therefore, AC = √(l2 + x2) and CB = √(m2 + f2 +x2 – 2fx). 2 It will then be the case that d√(l2 + x2) + e√(m2 + f2 + x2 – 2fx is equal to a minimum. Therefore, through my method of tangents it is the case that: (2dx/(√(l2 +x2)(AC))) + ((2ex -2ef)/ (√(m2 +f2 +x2 +2fx)(BC))) = 0. That is, it will be the case that AC/BC = dx/e(f-x). Now if we suppose that AC and BC are equal, it will be the case that f – x is to x, as d to e. Therefore, if a circle, with its center at C, is described by the ray CA or CB, AD or “x,” – the sine of the angle of incidence – will be to BE or “f – x,” – the sine of the angle of refraction – as e, the density of the medium of refraction, will be to d, the density of the medium of incidence, that is, the sines of the angles will be in reciprocal relation to the mediums or densities. (shrink)

BackgroundCo-creation allows to develop tailored interventions in chronicity and to increase patients’ engagement. Considering the interacting nature of physical, psychological, and social domains in multiple sclerosis, a biopsychosocial approach to care is crucial.AimsThis paper aims to present an example of a co-creation process in the context of chronic diseases preferences and perspectives of young adults with multiple sclerosis and healthcare professionals on the relevance, objectives, and modalities of a biopsychosocial intervention and on strategies/barriers to participation.MethodsA participatory mixed-method approach in three (...) consecutive steps was implemented: online surveys with YawMS and HCPs, online focus groups with YawMS, consultation with an advisory board composed by YawMS, HCPs and researchers. For the survey, descriptive statistics and inductive content analysis have been used for quantitative and qualitative analysis, respectively. FGs and AB were used to deepen the understanding of the survey’s results.ResultsAn integrated intervention is extremely relevant according to the perspectives of the main stakeholders. Helping disease acceptance, providing stress management strategies, and supporting emotional expression emerged as the most relevant psychological objectives according to participants. Having tangible benefits, being tailored, and fostering interpersonal relationships emerged as the main preferred characteristics of physical activity. Preferences emerged on the modalities and timing of the intervention, with a venue unrelated to the disease strongly supported. Both HCPs and YawMS highlighted as the most valuable advantages of conducting the intervention online the increased accessibility, while the main limit was the restriction to social interaction. Accessibility and lack of time resulted as the main barriers to participation.ConclusionThe co-creation process gave valuable information on preferences and perspectives of main stakeholders on objectives, modalities, and strategies to improve participation which has been used in the design of the ESPRIMO biopsychosocial intervention. Those results might inform future intervention development in the field of chronicity. The current paper outlined a co-creation methodology which might be replicated in future research on other conditions of vulnerability. (shrink)

Short-term motor practice leads to plasticity in the primary motor cortex. The purpose of this study is to investigate the factors that determine the increase in corticospinal tract excitability after motor practice, with special focus on two factors; “the level of muscle activity” and “the presence/absence of a goal of keeping the activity level constant.” Fifteen healthy subjects performed four types of rapid thumb adduction in separate sessions. In the “comfortable task” and “forceful task”, the subjects adducted their thumb using (...) comfortable and strong forces. In the “comfortable with a goal task” and “forceful with a goal task”, subjects controlled the muscle activity at the same level as in the C and F, respectively, by adjusting the peak electromyographic amplitude within the target ranges. Paired associative stimulation, which combines peripheral nerve stimulation and transcranial magnetic stimulation, with an inter-stimulus interval of 25 ms was also done. Before and after the motor tasks and PAS25, TMS was applied to the M1. None of the four tasks showed any temporary changes in behavior, meaning no learning occurred. Motor-evoked potential amplitude increased only after the FG and it exhibited a positive correlation with the MEP increase after PAS25, suggesting that FG and PAS25 share at least similar plasticity mechanisms in the M1. Resting motor threshold decreased only after FG, suggesting that FG would also be associated with the membrane depolarization of M1 neurons. These results suggest task-dependent plasticity from the synergistic effect of forceful muscle activity and of setting a goal of keeping the activity level constant. (shrink)

In line with Ken Manders’s seminal account of Euclid’s diagrammatic method in the “The Euclidean Diagram,” two proof systems with a diagrammatic syntax have been advanced as formalizations of the method FG and Eu. In a paper examining Eu, Nathaniel Miller, the creator of FG, has identified a variety of technical problems with the formal details of Eu. This response shows how the problems are remedied.

The landscape of graduate science education is changing as efforts to diversify the professoriate have increased because academic faculty jobs at universities have grown scarce and more competitive. With this context as a backdrop, the present research examines the perceptions and career goals of advisors and advisees through surveys of PhD students and faculty mentors in science, technology, engineering, and math disciplines. Study 1 examined actual preferences and career goals of PhD students among three options: research careers, teaching careers, and (...) non-academic careers in industry, and compared the actual preferences of students with what they perceived as being the normative preferences of faculty. Overall, students had mixed preferences but perceived that their advisors had a strong normative preference for research careers for them. Moreover, students who ranked research positions as most desirable felt the most belonging in their academic departments. Further analyses revealed no differences in career preferences as a function of underrepresented minority student status or first-generation status, but URM and FG students felt less belonging in their academic departments. Study 2 examined faculty preferences for different careers for their advisees, both in general and for current students in particular. While faculty advisors preferred students to go into research in general, when focusing on specific students, they saw their preferences as being closely aligned with the career preference of each PhD student. Faculty advisors did not perceive any difference in belonging between their students as a function of their URM status. Discrepancies between student and faculty perceptions may occur, in part, because faculty and students do not engage in sufficient discussions about the wider range of career options beyond academic research. Supporting this possibility, PhD students and faculty advisors reported feeling more comfortable discussing research careers with each other than either non-academic industry positions or teaching positions. Discussion centers on the implications of these findings for interpersonal and institutional efforts to foster diversity in the professoriate and to create open communication about career development. (shrink)

Background: Family therapy is considered as the gold standard in treatment of adolescents with anorexia nervosa (AN). Among the different types of family therapy, multi-family therapy (MFT) is increasingly used for treating AN, and shows promising results. In this article, our focus relied on the patients’ and their parents’ perceptions of the effectiveness and the underlying mechanisms of the MFT. Methods: The present pilot exploratory qualitative study included two focus groups conducted using a semi-structured approach: one with the adolescents (n= (...) 3), and another with one or two of their parents (n= 4 mothers;n= 2 fathers). The subjects discussed were the changes observed in both AN symptoms and family interactions following therapy, and the mechanisms underlying these changes. We crossed the perspectives of the adolescents and of the parents on these two points. Results: Qualitative analysis revealed that while both adolescents and parents had difficulties relating the changes they observed in the last year to MFT, they were able to say that the group cohesion had several positive effects and that their family dynamics had improved. In the light of analysis the adolescents perceived more improvements related eating disorders symptoms than their parents did, while parents were concerned about a negative effect of MFT on their children. Discussion: While both patients and parents perceived improvements in both AN symptoms and family interactions in the past year, it was not clear if they considered MFT to have led to these improvements. FG also explored the MFT mechanisms underlying changes. Both adolescents and their parents stressed the beneficial effects of identification to others members of the group and shared experience to overcome social isolation. Parents also mentioned the sympathy they felt for each other. The idea that they give a central place to families in the therapy was also described by the families. (shrink)

Skolem studied the germs at infinity of the smallest class of real valued functions on the positive real line containing the constant $1$, the identity function ${\mathbf {x}}$, and such that whenever f and g are in the set, $f+g,fg$ and $f^g$ are in the set. This set of germs is well ordered and Skolem conjectured that its order type is epsilon-zero. Van den Dries and Levitz computed the order type of the fragment below $2^{2^{\mathbf {x}}}$. Here we prove that (...) the set of asymptotic classes within any Archimedean class of Skolem functions has order type $\omega $. As a consequence we obtain, for each positive integer n, an upper bound for the fragment below $2^{n^{\mathbf {x}}}$. We deduce an epsilon-zero upper bound for the fragment below $2^{{\mathbf {x}}^{\mathbf {x}}}$, improving the previous epsilon-omega bound by Levitz. A novel feature of our approach is the use of Conway’s surreal number for asymptotic calculations. (shrink)

Skolem studied the germs at infinity of the smallest class of real valued functions on the positive real line containing the constant $1$, the identity function ${\mathbf {x}}$, and such that whenever f and g are in the set, $f+g,fg$ and $f^g$ are in the set. This set of germs is well ordered and Skolem conjectured that its order type is epsilon-zero. Van den Dries and Levitz computed the order type of the fragment below $2^{2^{\mathbf {x}}}$. Here we prove that (...) the set of asymptotic classes within any Archimedean class of Skolem functions has order type $\omega $. As a consequence we obtain, for each positive integer n, an upper bound for the fragment below $2^{n^{\mathbf {x}}}$. We deduce an epsilon-zero upper bound for the fragment below $2^{{\mathbf {x}}^{\mathbf {x}}}$, improving the previous epsilon-omega bound by Levitz. A novel feature of our approach is the use of Conway’s surreal number for asymptotic calculations. (shrink)