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The Janus kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathway is essential for cellular signal transduction, regulating immune responses, hematopoiesis, and cell proliferation. Dysregulation of JAK-STAT signaling due to genetic variations, particularly missense mutations, has been implicated in autoimmune disorders, cancers, and hematological malignancies. This study investigates missense mutations in JAK and STAT genes, focusing on disease-associated single nucleotide polymorphisms (SNPs) and ClinVar benign variants identified in the All of Us and COSMIC databases. We analyzed the distribution of these mutations across functional domains, their structural localization, and biochemical properties. We identified mutation hotspots within specific domains, highlighting their correlation with disease phenotypes. Structural mapping revealed that disease-associated SNPs predominantly localize in linker regions and at the boundaries of secondary structures, suggesting a significant impact on folding, stability, and function of JAK and STAT proteins. Additionally, we examined the genomic context of mutations and identified vulnerable sequences; for example, ‘GATC’. Furthermore, our analysis found no predominant association between potential CRISPR-Cas9 target sites and ClinVar benign/disease-associated SNPs. The analysis of amino acid sequence patterns surrounding mutations uncovered an enrichment of hydrophobic residues leucine (Leu), isoleucine (Ile), methionine (Met), and phenylalanine (Phe) in close proximity to disease-associated mutations. Our findings emphasize the importance of structural and biochemical context in determining pathogenicity. In this study, we provide a bioinformatic strategy for refining variant classification and understanding the roles of JAK-STAT pathway mutations in disease.
In this chapter, the author discusses the contemporary tensions of social change inspired by the Polanyian concept of the double movement. He interprets the double movement as a simultaneous combination of dis-embeddedness which destroys established social bonds and habits in order to accommodate new market opportunities, and re-embeddedness creating new social bonds and institutions. The author locates the interpretative frame in a more precise historical and sociocultural context where the double movement happens within the present globalised and individualised processes of change in the industrially advanced countries. He discusses the current perspectives of contemporary societies and the possibility of capitalism ending. The author considers the European context, while not ignoring the impact of global interdependence. He elaborates the analysis in order to take into account the effects of the long-lasting economic and financial crisis.
This section presents an annotated critical edition of En este país , one of the ‘artículos de costumbres’, a type of satirical sketch that was popular in nineteenth-century Europe, by the Romantic journalist Mariano José de Larra (1809–37).
This chapter draws authors own experiences of researching and writing about British women missionaries in South India during the nineteenth century. Writing a feminist history of white women and colonialism sensitive to issues of difference involves more than capturing the complex qualities of hierarchy embedded in past narratives. The missionary texts recount a story about Indian women and the efforts of British 'ladies' to emancipate them from the bounds of both culture and religion. Talal Asad's critique of anthropological translations raises a number of points relevant to Hayden White's historical method. White's depiction of historical writing as fictional remains an accurate and important qualifier to the issues of power and meaning raised by Asad and Edward Said. The missionary discourse of women's work is revealed as a process of 'othering' which constructs Indian women as converse of their free and active British sisters through the image of the zenana victim.
We present a new variational formulation for viscous and resistive Hall magnetohydrodynamics. We first find a variational principle for ideal Hall magnetohydrodynamics by applying the physical assumptions leading to Hall magnetohydrodynamics at the Lagrangian level, and then we add the viscous and resistive terms by means of constrained variations. We also provide a metriplectic reformulation of our formulation, based on two canonical Lie–Poisson brackets for the ideal part and metric 4-brackets for the dissipative part.
Mass gathering events represent complex operational environments that challenge emergency preparedness and prehospital medical response systems. Milano Pride, Italy’s largest LGBTQIA+ event, attracts over 300,000 attendees annually and combines a dynamic parade with a high-density static concert. This study reports a 3-year experience (2022-2024) of prehospital organization, operational deployment, and patient presentation patterns during the event.
Methods
A retrospective observational study was conducted using data from medical action plans, mission reports, and patient records collected during the final day of Milano Pride from 2022 to 2024. The integrated response system included 6 Basic Life Support ambulances, one Advanced Life Support unit, foot and bicycle rescue teams, a field hospital, and a centralized command center.
Results
A total of 165 missions were recorded across the 3 editions. Most cases were minor and managed on site; 8-20% required field hospital care and ≤7% hospital transport. Substance- and alcohol-related presentations accounted for approximately one quarter of cases annually. Trauma-related cases decreased over time. The mean patient age was 32 years, and the medical incident rate (0.17-0.20 per 1,000 participants) was lower than rates reported for comparable international events.
Conclusions
A structured, multidisciplinary prehospital system ensured effective on-site care while minimizing hospital impact, highlighting the importance of proactive planning and coordinated response in large urban mass gatherings.
The Charlotte Brontes were big business upon the 1930s stage. Adaptations of the sisters' novels, particularly Charlotte's Jane Eyre, had always been popular at the box office; but from the late 1920s, there was an unprecedented biodrama boom. This chapter explores Bronte biodrama as a critically reflexive art: a notable example of popular culture in dialogue with scholarship, heritage and tourism. Following a brief survey of the public interest afforded to Bronte relics and remains during the 1920s and 1930s, two case studies are developed: Alfred Sangster's popular stage success, The Brontes and Rachel Ferguson's satirical failure, Charlotte Bronte. The provisional nature of biography and edition is highlighted by Shorter's position on Charlotte's time in Brussels and her relationship with Constantin Heger. Playwrights taking the Brontes as their subjects in the 1930s enjoyed access to more primary material than ever before: printed texts, commemorative spaces and museum objects.
This chapter seeks to reassert the presence of Charlotte Bronte in Brussels through analyses of literary tourists' accounts of their journeys to and around the Pensionnat Heger. Reading these narratives within a critical framework of literary tourism theory, the chapter aims to demonstrate how Brussels literary tourism is situated within and contributes to the Bronte legacy more broadly, particularly with regard to the parallel mythologisation of the Bronte sisters at Haworth parsonage. The chapter focuses on two themes that have emerged as the dominant issues at stake in the legacy of Bronte tourism at Haworth to date: gender and nation. While Haworth serves to reiterate Charlotte Bronte's place as an English, female writer, the chapter suggests that Brussels offers a space where an alternative narrative unfolds, one that offers possibilities for reading the crafting of female independence through cosmopolitan interactions.
The Murcia Twin Registry (MTR) has steadily expanded over two decades and has become a key resource for twin research in the Mediterranean region. The registry currently includes data from 3971 individual twins born between 1940 and 1999, as well as an associated biobank containing samples from 1586 participants. Its primary research focus is on health and health-related behaviors within a public health framework, covering areas such as lifestyle, health promotion, quality of life, and environmental factors. Across multiple waves of data collection, the MTR has compiled extensive and wide-ranging phenotypic data. These data can be further expanded and have strong potential for record linkage with other health databases, particularly those of the regional public health care system, including both primary and inpatient care. Efforts are also underway to establish record linkage with additional sources of information, such as the educational system. In the near future, the registry aims to expand its biobank and continue the collection of longitudinal data, as well as increasing the ability to collect additional data that could enrich the information from participants in the register.
This chapter focuses on the legal definition of 'race', an area riddled with Canadian imperialist thought and practice, at the moment when the issue of 'Eskimo status' was catapulted before the Supreme Court of Canada. The crucial question posed in the case was whether 'Eskimos' were 'Indians' under the Canadian constitutional framework. At the time, the affirmative decision was derisively labelled 'an absurd little mouse' by Diamond Jenness, a leading white Canadian anthropologist, who borrowed it from the Latin of Horace. The 'discovery' of 'blonde Eskimos' in a remote area near the Bering Strait set anthropological tongues to wagging in earnest, until researchers unveiled the puzzle. The federal government insisted that Eskimos were distinct from Indians, and that the cost should be shouldered by the province of Quebec.
This chapter focuses on Clive Barker's Tortured Souls and Mister B. Gone, which shows a sustained engagement with the body and continues to escape the boundaries of classic horror to form its own elaborate mythologies. The Cenobites, characters who straddle the line between the torturer and the tortured, are possibly Barker's most famous creation; their stories have developed over ten films and an equally impressive number of comics. Like Hellraiser, Tortured Souls proposes a new carnal mythology introducing a pantheon of transmogrified superhumans. Mister B. Gone opens with a three-word exhortation: 'Burn this book'. The experience of reading Mister B. Gone is framed around finding out more about terrific deeds and losing one's mind in the process. Mister B. Gone is more than a straightforward horror novel chronicling the life of a fictional demonic memory.
This chapter analyses the motives that caused institutions in the United Kingdom initially to encourage Indians to study in Britain. Britain's occupation of India was part of a global civilising process that had been taking place for millennia. If reformists' theories could become political practice, then there was no more obvious method than in the preparation of Indian candidates for the Indian Civil Service. To include Indians in the civilising mission fitted admirably the elitist notions of the reformist agenda. In 1867, the Conservative Secretary of State, Sir Stafford Northcote, created nine competitive scholarships to enable Indians to study at British universities for the exams. The history of the Gilchrist scholarships from 1866 to 1896 highlights the motives and contradictions in British policy toward Indians studying in the United Kingdom.
Whether listening to different talkers improves or impedes word identification has important implications for theory and practice. Yet, past research on children with hearing devices shows discrepant findings. This study tested 22 children with typical hearing (mean 5;0) and 20 with hearing devices (mean 4;11) on a remote, online 4-alternative forced-choice task (with a 4-picture display) delivered on iPads, with blocks containing 1 vs. 6 different talkers. All words were familiar to young children and were minimal pairs contrasting in voicing and place of articulation in the word-initial and word-final positions. Word identification was worse for place contrasts occurring word finally when listening to different talkers, but no effect was found for voicing contrasts. A consistent position effect was also found, where word identification was poorer across all word-final contrasts. However, no group differences were detected. These results suggest that even when listening to familiar words in good listening environments, the word-final position remains vulnerable to word misidentification, which can be further impeded by listening to different talkers. These effects impact children with and without hearing devices to a similar degree.