Search Results (8)

The present Perspective analyzes the remarkable evolution of the Amyloid Cascade Hypothesis 2.0 (ACH2.0) theory of Alzheimer’s disease (AD) since its inception a few years ago, as reflected in the diminishing role of amyloid-beta (Aβ) in the disease. In the initial iteration of the ACH2.0, Aβ-protein-precursor (AβPP)-derived intraneuronal Aβ (iAβ), accumulated to neuronal integrated stress response (ISR)-eliciting levels, triggers AD. The neuronal ISR, in turn, activates the AβPP-independent production of its C99 fragment that is processed into iAβ, which drives the disease. The second iteration of the ACH2.0 stemmed from the realization that AD is, in fact, a disease of the sustained neuronal ISR. It introduced two categories of AD—conventional and unconventional—differing mainly in the manner of their causation. The former is caused by the neuronal ISR triggered by AβPP-derived iAβ, whereas in the latter, the neuronal ISR is elicited by stressors distinct from AβPP-derived iAβ and arising from brain trauma, viral and bacterial infections, and various types of inflammation. Moreover, conventional AD always contains an unconventional component, and in both forms, the disease is driven by iAβ generated independently of AβPP. In its third, the current, iteration, the ACH2.0 posits that proteolytic production of Aβ is suppressed in AD-affected neurons and that the disease is driven by C99 generated independently of AβPP. Suppression of Aβ production in AD seems an oxymoron: Aβ is equated with AD, and the later is inconceivable without the former in an ingrained Amyloid Cascade Hypothesis (ACH)-based notion. But suppression of Aβ production in AD-affected neurons is where the logic leads, and to follow it we only need to overcome the inertia of the preexisting assumptions. Moreover, not only is the generation of Aβ suppressed, so is the production of all components of the AβPP proteolytic pathway. This assertion is not a quantum leap (unless overcoming the inertia counts as such): the global cellular protein synthesis is severely suppressed under the neuronal ISR conditions, and there is no reason for constituents of the AβPP proteolytic pathway to be exempted, and they, apparently, are not, as indicated by the empirical data. In contrast, tau protein translation persists in AD-affected neurons under ISR conditions because the human tau mRNA contains an internal ribosomal entry site in its 5′UTR. In current mouse models, iAβ derived from AβPP expressed exogenously from human transgenes elicits the neuronal ISR and thus suppresses its own production. Its levels cannot principally reach AD pathology-causing levels regardless of the number of transgenes or the types of FAD mutations that they (or additional transgenes) carry. Since the AβPP-independent C99 production pathway is inoperative in mice, the current transgenic models have no potential for developing the full spectrum of AD pathology. What they display are only effects of the AβPP-derived iAβ-elicited neuronal ISR. The paper describes strategies to construct adequate transgenic AD models. It also details the utilization of human neuronal cells as the only adequate model system currently available for conventional and unconventional AD. The final alteration of the ACH2.0, introduced in the present Perspective, is that AβPP, which supports neuronal functionality and viability, is, after all, potentially produced in AD-affected neurons, albeit not conventionally but in an ISR-driven and -compatible process. Thus, the present narrative begins with the “omnipotent” Aβ capable of both triggering and driving the disease and ends up with this peptide largely dislodged from its pedestal and retaining its central role in triggering the disease in only one, although prevalent (conventional), category of AD (and driving it in none). Among interesting inferences of the present Perspective is the determination that “sporadic AD” is not sporadic at all (“non-familial” would be a much better designation). The term has fatalistic connotations, implying that the disease can strike at random. This is patently not the case: The conventional disease affects a distinct subpopulation, and the basis for unconventional AD is well understood. Another conclusion is that, unless prevented, the occurrence of conventional AD is inevitable given a sufficiently long lifespan. This Perspective also defines therapeutic directions not to be taken as well as auspicious ways forward. The former category includes ACH-based drugs (those interfering with the proteolytic production of Aβ and/or depleting extracellular Aβ). They are legitimate (albeit inefficient) preventive agents for conventional AD. There is, however, a proverbial snowball’s chance in hell of them being effective in symptomatic AD, lecanemab, donanemab, and any other “…mab” or “…stat” notwithstanding. They comprise Aβ-specific antibodies, inhibitors of beta- and gamma-secretase, and modulators of the latter. In the latter category, among ways to go are the following: (1) Depletion of iAβ, which, if sufficiently “deep”, opens up a tantalizing possibility of once-in-a-lifetime preventive transient treatment for conventional AD and aging-associated cognitive decline, AACD. (2) Composite therapy comprising the degradation of C99/iAβ and concurrent inhibition of the neuronal ISR. A single transient treatment could be sufficient to arrest the progression of conventional AD and prevent its recurrence for life. Multiple recurrent treatments would achieve the same outcome in unconventional AD. Alternatively, the sustained reduction/removal of unconventional neuronal ISR-eliciting stressors through the elimination of their source would convert unconventional AD into conventional one, preventable/treatable by a single transient administration of the composite C99/iAβ depletion/ISR suppression therapy. Efficient and suitable ISR inhibitors are available, and it is explicitly clear where to look for C99/iAβ-specific targeted degradation agents—activators of BACE1 and, especially, BACE2. Directly acting C99/iAβ-specific degradation agents such as proteolysis-targeting chimeras (PROTACs) and molecular-glue degraders (MGDs) are also viable options. (3) A circumscribed shift (either upstream or downstream) of the position of transcription start site (TSS) of the human AβPP gene, or, alternatively, a gene editing-mediated excision or replacement of a small, defined segment of its portion encoding 5′-untranslated region of AβPP mRNA; targeting AβPP RNA with anti-antisense oligonucleotides is another possibility. If properly executed, these RNA-based strategies would not interfere with the protein-coding potential of AβPP mRNA, and each would be capable of both preventing and stopping the AβPP-independent generation of C99 and thus of either preventing AD or arresting the progression of the disease in its conventional and unconventional forms. The paper is interspersed with “validation” sections: every conceptually significant notion is either validated by the existing data or an experimental procedure validating it is proposed. Full article

This article aims to offer Yi Kwangsu’s The Heartless (Mujŏng, 1917), the first modern Korean novel, as an emblem of hybrid religiosity in colonial modernity that sheds light on an ambivalent alterity in the problem of hell in non-Western cultures. To the extent that the problem of hell in Christianity pertains to the question of why God allows evil to exist eternally, God’s omnipotent authority with justice and fairness beyond the grave is placed at the center of the inquiry into the ultimate standard of moral goodness the religious feasibility of which justifies the existence of sinners suffering eternal damnation in hell. But the co-existence of the omnipotent God and unrepentant sinners is not always questioned in the religiosity of hell in non-Western cultures. The Christian imaginary of hell in non-Western cultures often demarcates the question of God’s sovereignty from the sufferings of sinners in the problem of hell. Based on these observations, this article will investigate Yi’s narratives of hell in The Heartless, which are associated with Christianity but intertwined with his ethical demands for shaping a new individuality beyond the traditional hybrid religiosity of hell. Specifically, first, we will show that Yi’s Christian imaginary of hell is reformulated through the traditional imaginaries of hell in which, regardless of the existence of God’s sovereignty over the created order, the sufferings of sinners in hell function to secure social norms and orders. In doing so, we claim that the Christian imaginary of hell in The Heartless is relegated to a rhetorical means to beget the need for the self-awakening of the inner-self through which individual desires can be freed from the influences of Confucian morality as well as Christian theodicy. Second, in comparison with Lu Xun’s sympathetic relocation of Christian spirituality within the traditional Chinese imaginaries of hell in his longing for modern subjectivity, we explore Yi’s hybrid religiosity within colonial modernity, the vitality of which cannot be confined within the simple dichotomy between Western and non-Western cultures. At this juncture, the upshot of Yi’s hybrid religiosity within colonial modernity is that the theodicy of hell in Christianity can be displaced and thereby disenfranchised from the centrality of the search for a new individuality. Full article

The unprecedented wildfires of 2017 in Portugal, particularly affecting the Centre Region, resulted in more than 100 deaths and numerous other dramatic socioeconomic and environmental impacts. Due to the unparalleled magnitude of these events, the extent of the burned area, and the catastrophic consequences, forest and fire management were placed at the center stage of public and political concerns, receiving wide mass media attention and amplification likely to shape public opinion and influence policy decisions. Through a quasi-qualitative content analysis approach, this article focuses on the media narratives conveyed by the news issued over two years (N = 1056) by eight newspapers of different periodicities and geographical scopes regarding the wildfires of October 2017 in the Matas do Litoral—coastal public-managed forest areas located in the Centre Region of Portugal. The analysis focuses on three main dimensions: the agents and actors mentioned and their power-related positions, the geographical coverage of the newspapers, and the relevance ascribed to emotions and feelings in the media narratives about the wildfires. The results demonstrate the relevance attributed in media narratives to the views of institutional agents and the negligence of local people’s voices. When particularly highlighting the material impacts of the wildfires, media narratives tended to focus less on people’s emotions and other non-tangible issues. The variation in these narratives according to the geographical scope of the newspapers and the publication time of the news strongly points out the need to address the heterogeneous character of the media coverage of wildfires. Full article

This article explores the pictorial representation of the Buddhist hell in Kamakura (1185–1333) Japan, with a focus on a mid-thirteenth century rokudō-e, or Pictures of the Six Realms, preserved at Shōjuraigōji Temple. The examination revolves around how these scroll paintings convey messages of salvation by representing the symbolic architecture of the hell realm, the lowest level within the six realms. By scrutinizing the visual representation of hell landscapes in four hell scrolls in the Shōjuraigōji set, the study unveils the architectural symbolism of boundaries and pathways. A visual analysis of two hell-tearing narrative scrolls further reveals that the key iconography involves the destruction of the architectural symbols of hell. Through tracing the concurrent processes of constructing and destroying the imaginary space of hell, the study demonstrates that the conceptual and visual construction of hell is coupled with an equally pronounced intent for hell-tearing. Lastly, based on the visuality of the hell-escaping narratives, the medium of hanging scrolls, and the centrality of an Enma scroll within the Shōjuraigōji set, the author proposes a spatial arrangement of this set of fifteen scrolls that could systematically convey the visual massage of “escaping from suffering in the six courses”. Full article

Tales of Times Now Past (Konjaku Monogatarishū 今昔物語集) is a Japanese setsuwa (anecdotes) collection dating from the early twelfth century. Originally contained in 31 volumes, it includes more than one thousand systematically arranged tales from India, China, and Japan. Despite the fact that Daoism was rejected by the Japanese imperial court as an organized religion, Daoist philosophies and practical systems found their ways into Japan, having a significant and profound influence over Japanese esoteric cosmology and folk beliefs. This article takes the Lord of Mount Tai (CN: Taishan Fujun; JP: Taizan Fukun 泰山府君) as the focus and examines two pertinent stories in Tales of Times Now Past. By placing the texts in a broader historical, religious, and comparative Japan–China perspective, I examine the reshaping of Daoist elements and traditional Chinese philosophical principles in these two stories and thus demonstrate how the Daoist fragments transmitted to Japan were transformed into an integral part of the orthodox structure by the time of the late Heian period in the pursuit of a more organized form of government. Full article

Baojuan (precious scrolls) are a type of prosimetric literature in the vernacular language that flourished in the lower Yangzi valley between the late nineteenth and early twentieth centuries. Most baojuan texts are devoted to religious themes, often involving wondrous figures and events which can be characterized as “supernatural”. The Precious Scroll of Wang Hua (Wang Hua baojuan 王花寶卷) is a comparatively late text centered on the marvelous apparitions leading to the salvation of a lay person. It is a widespread text of the southern “scroll recitation” tradition as it survives in Changshu, Jiangsu, but to date, it has not received attention from scholars of Chinese popular literature and religion. Still, it is important for understanding the origins, development, and functions of precious scrolls and their contribution to the field of Chinese popular religion. The original text of the Precious Scroll of Wang Hua formed ca. end of the nineteenth century, but the present research mainly uses the manuscript version of a modern performer from the vicinity of Changshu (ca. 1995). This narrative combines two major topics of the wondrous manifestation of Bodhisattva Guanyin and the descent to Hell. Both topics can be traced back to the early “miracle tales”. Here, they have been adapted to the local life and cultural setting. The figure of the skeptical and egoistic Wang Hua who initially rejected the injunctions of Guanyin is a type well known to the modern audiences of baojuan. Thus, the supernatural elements serve the purpose of reconfirming traditional beliefs and values in the contemporary society. Full article

Background: Illness narratives with meaningful, competent and targeted content have been shown to provide useful guides for patient decision-making and have positive influences on health behaviors. The use of narratives in decision aids can confer a sense of structure, plot and context to illness experiences and help patients make treatment decisions that feel sensible, informed, and transparent. Aim: This paper presents narratives of suffering and healing from patients and their caregivers with advanced heart failure who engaged in decision-making regarding Left Ventricular Device Assist (LVAD) treatment. Methods: Narratives were collected from in-depth interviews with patients who accepted (n = 15) versus declined (n = 15) LVAD implant, LVAD candidates who had received education about LVAD and were in the process of making a decision (n = 15), and caregivers (family or significant others) of LVAD patients (n = 15). Results: Participants shared “restitution” narratives that most commonly conveyed a shift from pre-implant physical suffering and “daily hell,” fatigue so intense it “hurts,” along with emotional suffering from inability to engage with the world, to post-implant improvements in mobility and quality of life, including positivity and family support, adaptation on a “journey,” “getting one’s life back” and becoming “normal” again. Conclusion: For LVAD patients, other patients’ illness narratives can help to give meaning to their own illness and treatment experiences and to more accurately forecast treatment impacts on lifestyle and identity. For clinicians, patient narratives can enhance patient–practitioner communication and understanding by highlighting perspectives and values that structure patients’ clinical experiences. Full article

Cultural constructions of passive motherhood, especially within domestic spaces, gained currency in India and Ireland due to their shared colonial history, as well as the influence of anti-colonial masculinist nationalism on the social imaginary of these two nations. However, beginning from the latter half of the nineteenth century, postcolonial literary voices have not only challenged the traditional gendering of public and private spaces but also interrogated docile constructions of womanhood, particularly essentialized representations of maternity. Domestic spaces have been critical narrative motifs in these postcolonial texts through simultaneously embodying patriarchal domination but also as sites where feminist resistance can be actualized by “transgress(ing) traditional views of … the home, as a static immobile place of oppression”. This paper, through a comparative analysis of maternal characters in Edna O’Brien’s The Love Object and Jhumpa Lahiri’s Hell-Heaven, argues that socially disapproved/illicit relationships in these two representative postcolonial Irish and Indian narratives function as matricentric feminist tactics that subvert limiting notions of both domestic spaces and gendered liminal postcolonial subjectivities. I highlight that within the context of male-centered colonial and nationalist literature, the trope of maternity configures the domestic-space as the “rightful place” for the existence of the feminine entity. Thus, when postcolonial feminist fiction reverses this tradition through constructing the “home and the female-body” as sites of possible resistance, it is a counter against dual oppression: both colonialism and patriarchy. My intervention further underscores the need for sustained conversations between the literary output of India and Ireland, within Postcolonial Literary Studies, with a particular acknowledgement for space and gender as pivotal categories in the “cultural analysis of empire”. Full article