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This article examines the production of musical nostalgia in High School Musical: The Musical: The Series (2019–23), one of the first series created for Disney’s streaming platform. On one level, the series serves as a nostalgic extension of the High School Musical franchise in its setting and narrative construction, and a nostalgic continuation of the teen-musical genre in its idealised depiction of high-school life mediated through song. At the same time, this nostalgia is coupled with an emphasis on the show’s newness: the series transposes the original film to a new format—a self-referential, multi-episodic mockumentary—and occupies a different temporal world, in which nostalgia is technologically mediated and constructed as part of the diegesis. Focusing on music, as a primary sensory input for the evocation of nostalgia, this study explores how The Series capitalises upon this nostalgia/modernity dichotomy to structure its narrative and engender brand affinity. Drawing together textual analyses of audiovisual sequences and practitioner testimony from the show’s creatives, it demonstrates how The Series uses music to develop Disney’s brand, harnessing the technological and creative promise of the Company’s proprietary streaming service, whilst simultaneously employing nostalgic strategies to reaffirm the status quo in aspects of its narrative.

This article examines the website Vocabulous, an innovative resource that combines Classics and English literacy. The aim of Vocabulous is to improve students' English vocabulary knowledge and skills using Latin and Greek root patterns. For example, the root ‘scrip’ meaning ‘write’ can help students understand that ‘inscription’, ‘manuscript’ and ‘transcription’ are all related to writing. Students use these roots to work out the meaning of unfamiliar vocabulary, so that by the end of the programme, they have the skills they need to decipher new words on their own. As Alex Quigley notes, ‘over 90% of the vocabulary of academic texts in school has Latin and Greek origins and therefore teaching etymology has positive implications for learning and cracking the academic code of school’ (Quigley, 2018: 71). This article discusses the pedagogy behind the site, the selection of Latin and Greek roots, the design of the questions (based on vocabulary acquisition research) and the use of animated videos to engage students. The article concludes by outlining the current Vocabulous trial with 10–13-year-olds in 50 schools across the UK, combining teacher testimonies with ideas for practical application in the classroom1. Vocabulous is funded by The SHINE Trust and is part of a research trial led by Professor Arlene Holmes-Henderson and Christ Church, Oxford. It will be available for school subscriptions from September 2023.

Abstract During sleep, recent memories are replayed by the hippocampus, leading to their consolidation, with a higher priority given to salient experiences. To examine the role of replay in the selective strengthening of memories, we recorded large ensembles of hippocampal place cells while male rats ran repeated spatial trajectories on two linear tracks, differing in either their familiarity or number of laps run. We observed that during sleep, the rate of replay events for a given track increased proportionally with the number of spatial trajectories run by the animal. In contrast, the rate of sleep replay events decreased if the animal was more familiar with the track. Furthermore, we find that the cumulative number of awake replay events occurring during behavior, influenced by both the novelty and duration of an experience, predicts which memories are prioritized for sleep replay, providing a more parsimonious neural correlate for the selective strengthening of memories.

Niemann Pick diseases types A (NPDA) and C (NPDC) are lysosomal storage disorders (LSDs) leading to cognitive impairment, neurodegeneration, and early death. NPDA and NPDC have different genetic origins, being caused by mutations in the acid sphingomyelinase (ASM) or the cholesterol transport protein NPC1, respectively. However, they share a common pathological hallmark in the accumulation of lipids in the endolysosomal compartment. Here, we tested the hypothesis that polyphenols reduce lipid overload in NPD cells by enhancing the secretion of extracellular vesicles (ECVs). We show that among the polyphenols tested, the ellagic acid metabolites, urolithin A and B, were the safest and most efficient in increasing ECV secretion. They reduced levels of accumulating lipids and lysosomal size and permeabilization in cultured bone marrow-derived macrophages and neurons from ASMko and NPC1 mutant mice, which mimic NPDA and NPDC, respectively. Moreover, oral treatment with ellagic acid reduced lipid levels, ameliorated lysosomal alterations, and diminished microglia activation in the brain of NPD mice. These results support the therapeutic value of ECV secretion and polyphenols for NPDs, which may also help treat other LSDs characterized by intracellular lipid overload.

Niemann-Pick disease type A (NPD-A) is a lysosomal storage disorder characterized by neurodegeneration and early death. It is caused by loss-of-function mutations in the gene encoding for acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin into ceramide. Here, we evaluated the safety of cerebellomedullary (CM) cistern injection of adeno-associated viral vector serotype 9 encoding human ASM (AAV9-hASM) in nonhuman primates (NHP). We also evaluated its therapeutic benefit in a mouse model of the disease (ASM-KO mice). We found that CM injection in NHP resulted in widespread transgene expression within brain and spinal cord cells without signs of toxicity. CM injection in the ASM-KO mouse model resulted in hASM expression in cerebrospinal fluid and in different brain areas without triggering an inflammatory response. In contrast, direct cerebellar injection of AAV9-hASM triggered immune response. We also identified a minimally effective therapeutic dose for CM injection of AAV9-hASM in mice. Two months after administration, the treatment prevented motor and memory impairment, sphingomyelin (SM) accumulation, lysosomal enlargement, and neuronal death in ASM-KO mice. ASM activity was also detected in plasma from AAV9-hASM CM-injected ASM-KO mice, along with reduced SM amount and decreased inflammation in the liver. Our results support CM injection for future AAV9-based clinical trials in NPD-A as well as other lysosomal storage brain disorders.

Replay, the sequential reactivation within a neuronal ensemble, is a central hippocampal mechanism postulated to drive memory processing. While both rate and place representations are used by hippocampal place cells to encode behavioral episodes, replay has been largely defined by only the latter – based on the fidelity of sequential activity across neighboring place fields. Here, we show that dorsal CA1 place cells in rats can modulate their firing rate between replay events of two different contexts. This experience-dependent phenomenon mirrors the same pattern of rate modulation observed during behavior and can be used independently from place information within replay sequences to discriminate between contexts. Our results reveal the existence of two complementary neural representations available for memory processes.

Background & Aims: The molecular mechanisms driving the progression from early-chronic liver disease (CLD) to cirrhosis and, finally, acute-on-chronic liver failure (ACLF) are largely unknown. Our aim was to develop a protein network-based approach to investigate molecular pathways driving progression from early-CLD to ACLF. Methods: Transcriptome analysis was performed on liver biopsies from patients at different liver disease stages, including fibrosis, compensated cirrhosis, decompensated cirrhosis and ACLF, and control healthy livers. We created 9 liver-specific disease-related protein-protein interaction networks capturing key pathophysiological processes potentially related to CLD. We used these networks as a framework and performed gene set-enrichment analysis (GSEA) to identify dynamic gene profiles of disease progression. Results: Principal component analyses revealed that samples clustered according to the disease stage. GSEA of the defined processes showed an upregulation of inflammation, fibrosis and apoptosis networks throughout disease progression. Interestingly, we did not find significant gene expression differences between compensated and decompensated cirrhosis, while ACLF showed acute expression changes in all the defined liver disease-related networks. The analyses of disease progression patterns identified ascending and descending expression profiles associated with ACLF onset. Functional analyses showed that ascending profiles were associated with inflammation, fibrosis, apoptosis, senescence and carcinogenesis networks, while descending profiles were mainly related to oxidative stress and genetic factors. We confirmed by qPCR the upregulation of genes of the ascending profile and validated our findings in an independent patient cohort. Conclusion: ACLF is characterized by a specific hepatic gene expression pattern related to inflammation, fibrosis, apoptosis, senescence and carcinogenesis. Moreover, the observed profile is significantly different from that of compensated and decompensated cirrhosis, supporting the hypothesis that ACLF should be considered a distinct entity. Lay summary: By using transjugular biopsies obtained from patients at different stages of chronic liver disease, we unveil the molecular pathogenic mechanisms implicated in the progression of chronic liver disease to cirrhosis and acute-on-chronic liver failure. The most relevant finding in this study is that patients with acute-on-chronic liver failure present a specific hepatic gene expression pattern distinct from that of patients at earlier disease stages. This gene expression pattern is mostly related to inflammation, fibrosis, angiogenesis, and senescence and apoptosis pathways in the liver.

Maximum heart rate (MHR) is widely used in the prescription and monitoring of exercise intensity, and also as a criterion for the termination of sub-maximal aerobic fitness tests in clinical populations. Traditionally, MHR is predicted from an age-based formula, usually 220-age. These formulae, however, are prone to high predictive errors that potentially could lead to inaccurately prescribed or quantified training or inappropriate fitness test termination. In this paper, we used functional data analysis (FDA) to create a new method to predict MHR. It uses heart rate data gathered every 5 seconds during a low intensity, sub-maximal exercise test. FDA allows the use of all the information recorded by monitoring devices in the form of a function, reducing the amount of information needed to generalize a model, besides minimizing the curse of dimensionality. The functional data model created reduced the predictive error by more than 50% compared to current models within the literature. This new approach has important benefits to clinicians and practitioners when using MHR to test fitness or prescribe exercise.

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Abstract Fatty-acid-binding proteins (FABPs) are small intracellular proteins that coordinate lipid-mediated processes by targeting metabolic and immune response pathways. The aim of the study was to investigate plasma FABPs levels and their relationship with clinical outcomes in cirrhosis. Plasma levels of L-FABP1(liver and kidney), I-FABP2(intestine), and A-FABP4(adipocyte and macrophages) were measured in 274 patients with decompensated cirrhosis. Hepatic gene expression of FABPs was assessed in liver biopsies from patients with decompensated cirrhosis and in liver cell types from mice with cirrhosis. Immunohistochemistry of A-FABP4 in human liver biopsy was also performed. Plasma levels of FABPs were increased in patients with decompensated cirrhosis compared to those of healthy subjects (L-FABP1: 25 (17–39) vs 10 (9–17) ng/mL p = 0.001, I-FABP2: 1.1 (0.5–2.1) vs 0.6 (0.4–1) ng/mL p = 0.04 and A-FABP4: 37 (20–68) vs 16 (11–33) ng/mL p = 0.002), respectively. Increased A-FABP4 levels were associated with complications of cirrhosis, acute-on-chronic liver failure and poor survival. Hepatic A-FABP4 gene expression was upregulated in decompensated cirrhosis. Macrophages were the main liver cell that over-expressed A-FABP4 in experimental cirrhosis and increased A-FABP4 was found in macrophages of human biopsies by immunohistochemistry. A-FABP4 levels are increased in decompensated cirrhosis and correlate with poor outcomes. Liver macrophages appear to be the main source of A-FABP4 in decompensated cirrhosis.

Liver disease resulting from heart failure (HF) has generally been referred as “cardiac hepatopathy”. One of its main forms is congestive hepatopathy (CH), which results from passive venous congestion in the setting of chronic right-sided HF. The current spectrum of CH differs from earlier reports with HF, due to ischemic cardiomyopathy and congenital heart disease having surpassed rheumatic valvular disease. The chronic passive congestion leads to sinusoidal hypertension, centrilobular fibrosis, and ultimately, cirrhosis (“cardiac cirrhosis”) and hepatocellular carcinoma after several decades of ongoing injury. Contrary to primary liver diseases, in CH, inflammation seems to play no role in the progression of liver fibrosis, bridging fibrosis occurs between central veins to produce a “reversed lobulation” pattern and the performance of non-invasive diagnostic tests of liver fibrosis is poor. Although the clinical picture and prognosis is usually dominated by the underlying heart condition, the improved long-term survival of cardiac patients due to advances in medical and surgical treatments are responsible for the increased number of liver complications in this setting. Eventually, liver disease could become as clinically relevant as cardiac disease and further complicate its management.

The concept of liver fibrosis and cirrhosis being static and therefore irreversible is outdated. Indeed, both human and animal studies have shown that fibrogenesis is a dynamic and potentially reversible process that can be modulated either by stopping its progression and/or by promoting its resolution. Therefore, the study of the molecular mechanisms involved in the pathogenesis of liver fibrosis is critical for the development of future antifibrotic therapies. The fibrogenesis process, common to all forms of liver injury, is characterized by the increased deposition of extracellular matrix components (EMCs), including collagen, proteoglycans, and glycoproteins (laminin and fibronectin 2). These changes in the composition of the extracellular matrix components alter their interaction with cell adhesion molecules, influencing the modulation of cell functions (growth, migration, and gene expression). Hepatic stellate cells and Kupffer cells (liver macrophages) are the key fibrogenic effectors. The antifibrogenic mechanism starts with the activation of Ly6Chigh macrophages, which can differentiate into macrophages with antifibrogenic action. The research of biochemical changes affecting fibrosis irreversibility has identified lysyl oxidase-like 2 (LOXL2), an enzyme that promotes the network of collagen fibers of the extracellular matrix. LOXL2 inhibition can decrease cell numbers, proliferation, colony formations, and cell growth, and it can induce cell cycle arrest and increase apoptosis. The development of a new humanized IgG4 monoclonal antibody against LOXL2 could open the window of a new antifibrogenic treatment. The current therapeutic target in patients with liver cirrhosis should focus (after the eradication of the causal agent) on the development of new antifibrogenic drugs. The development of these drugs must meet three premises: Patient safety, in non-cirrhotic phases, down-staging or at least stabilization and slowing the progression to cirrhosis must be achieved; whereas in the cirrhotic stage, the objective should be to reduce fibrosis and portal pressure.

MCP-1 (monocyte chemoattractant protein-1) is a proinflammatory cytokine involved in chemotaxis of monocytes. In several diseases, such as acute coronary syndromes and heart failure, elevated MCP-1 levels have been associated with poor outcomes. Little is known about MCP-1 in cirrhosis.To investigate the relationship between MCP-1 and outcome in decompensated cirrhosis.Prospective study of 218 patients discharged from hospital after an admission for complications of cirrhosis. Urine and plasma levels of MCP-1 and other urine proinflammatroy biomarkers: osteopontin(OPN), trefoil-factor3 and liver-fatty-acid-binding protein were measured at admission. Urine non-inflammatory mediators cystatin-C, β2microglobulin and albumin were measured as control biomarkers. The relationship between these biomarkers and the 3-month hospital readmission, complications of cirrhosis, and mortality were assessed.69 patients(32%) had at least one readmission during the 3-month period of follow-up and 30 patients died(14%). Urine MCP-1 and OPN levels, were associated with 3-month probability of readmission (0.85 (0.27-2.1) and 2003 (705-4586) ug/g creat vs 0.47 (0.2-1.1) and 1188 (512-2958) ug/g creat, in patients with and without readmission, respectively; p

Biomarkers are potentially useful in assessment of outcomes in patients with cirrhosis, but information is very limited. Given the large number of biomarkers, adequate choice of which biomarker(s) to investigate first is important.Analysis of potential usefulness of a panel of urinary biomarkers in outcome assessment in cirrhosis.Fifty-five patients with acute decompensation of cirrhosis were studied: 39 had Acute Kidney Injury (AKI) (Prerenal 12, type-1 HRS (hepatorenal syndrome) 15 and Acute Tubular Necrosis (ATN) 12) and 16 acute decompensation without AKI. Thirty-four patients had Acute-on-chronic liver failure (ACLF). A panel of 12 urinary biomarkers was assessed, using a multiplex assay, for their relationship with ATN, ACLF and mortality.Biomarker with best accuracy for ATN diagnosis was NGAL (neutrophil-gelatinase associated lipocalin): 36 [26-125], 104 [58-208] and 1807 [494-3,716] μg/g creatinine in Prerenal-AKI, type-1 HRS and ATN, respectively; p

Abstract Background Knowledge of haematological abnormalities in cirrhosis has greatly improved in recent years. Aims To evaluate how Spanish Digestive Disease specialists manage haemostatic alterations and associated disorders in patients with cirrhosis. Methods All members of the Spanish Association for the Study of the Liver and Spanish Society of Digestive Pathology were invited to fill in a web-based questionnaire. Results 135 professionals, 93 hepatologists and 42 non-hepatologists responded to the survey. The concept of rebalanced haemostasis was known by 74.8% of them. Most specialists corrected the INR and thrombocytopenia before invasive procedures with moderate risk of bleeding or major surgery and in severe gastrointestinal bleeding. The threshold of platelets and, especially, INR used to administer blood products varied greatly. Pharmacological prophylaxis of venous thromboembolism prevailed, but it was highly dependent on the INR and platelet figures. Most participants initiated anticoagulation regardless of the degree of portal vein thrombosis, even in patients ineligible for transplantation. In potential candidates, only 56% maintained it indefinitely or until liver transplantation. No major differences between hepatologists and non-hepatologists were found. Conclusions A significant variability and certain deviation from current guidelines was observed among Spanish Digestive Disease specialists regarding management of haemostatic alterations and associated disorders in cirrhosis. [ABSTRACT FROM AUTHOR]