Phillips University

This study examines exposition of the plot in Bapsi Sidhwa’s Ice-Candy Man (1988) and Water (2006) to introduce characters, settings, and central conflicts, serving as a precursor to the novels’ major thematic concerns. Employing a qualitative, interpretive approach grounded in Seymour Chatman’s structuralist narratology, particularly his distinction between story and discourse, the analysis explores the effect of expository passages on readers’ understanding of gender oppression, cultural memory, trauma, and ideological critique. In Water, the widow ashram functions as a symbol of patriarchal, religious, and economic subjugation, while Chuyia’s forced marriage reflects systemic discrimination. In Ice-Candy Man, the child narrator Lenny presents pre-Partition Lahore, subtly anticipating communal violence and the commodification of Ayah’s body. Exposition in both novels operates not as mere background but as a thematic device, establishing early ideological frameworks that reveal patriarchy, trauma, gender vulnerability, and cultural fragmentation.

This study explores how Dawn newspaper has represented major flood events in Pakistan, specifically focusing on the 2010, 2020, and 2022 floods, through the lens of ecolinguistics and critical discourse analysis (CDA). By analysing language use, metaphors, and framing techniques, the study explores how media discourse frames the causes of these floods, the role of human activities in exacerbating them, and how climate change is discussed in relation to these events. The findings show that while earlier reports (especially in 2010) essentially depicted floods as natural, inevitable events, recent coverage (2020 and 2022) has begun to acknowledge the role of human-induced factors, such as deforestation, poor urban planning, and inadequate disaster management, in intensifying the severity of these floods. Furthermore, the 2022 coverage demonstrated a shift towards incorporating climate change as a significant factor in the increasing frequency and intensity of these floods. Despite this shift, media coverage continues to primarily emphasise humanitarian impacts, such as loss of life and displacement, rather than exploring long-term structural solutions, including climate adaptation, sustainable infrastructure, and policy reforms. The study underscores the importance of media discourse in shaping public perceptions of environmental issues and argues for a more action-oriented, policy-driven approach to media coverage to encourage proactive responses to the growing threat of climate change and ecological degradation.

Novel variants of known natural product (NP) classes can provide valuable insights into their biosynthesis, mechanisms of action, and potential as drug leads across the entire class. Here, we describe a novel member of the widespread detoxine/rimosamide‐like (DRL) natural products, named pseudotetraivprolide, produced by Pseudomonas strains. Pseudotetraivprolide exhibits the characteristic DRL‐activity of protecting Bacillus cereus against the antibiotic blasticidin S. Through the generation of multiple deletion and complementation mutants, heterologous expression experiments, identification and structure elucidation of several derivatives, chemical synthesis of main derivatives, enzymatic characterization of individual biochemical steps, and detailed homology modelling of enzyme complexes, we elucidated key aspects of its biosynthesis. Our findings demonstrate that the primary metabolism‐derived malonyl CoA:ACP transacylase (FabD) functions as a trans‐AT in the biosynthesis pathway. Furthermore, we suggest an order for all late‐stage modifications and assign a function for the three conserved hypothetical proteins PipDFG acting as last‐step acetylation complex responsible for stabilization and activation of the final product.

Abstract Objective To compare the long-term effects of transcutaneous vagus nerve stimulation (tVNS) and invasive vagus nerve stimulation (iVNS) on seizure frequency and tolerability in patients with drug-resistant epilepsies. Methods A retrospective cohort study was conducted to compare the efficacy of iVNS vs. tVNS in patients with drug-resistant epilepsy. Treatment response was defined as a > 50% reduction in seizure frequency. Antiseizure medications (ASM) were continued and changed if deemed clinically necessary. Data were collected during outpatient visits or by telephone interview using a standardized questionnaire. The questionnaire covered various aspects, including seizure frequency, tolerability, adverse effects, mood, and quality of life. Results In total, 75 patients treated with VNS and ASM were included. In the VNS cohort, 18 patients (mean age 40.7 ± 15.49 years) were treated with tVNS and 57 patients (mean age 31.6 ± 11.15 years) used iVNS. The final analysis included 47 patients (53% male, 47% female) who had a follow-up period of 5 years for tVNS and 15 years for iVNS. In the tVNS treatment group the response rate was 30%, while in iVNS users the response rate was 32%. Kaplan–Meier analysis for iVNS and tVNS users revealed comparable effects over a 5-year period, with no statistically significant differences observed in response rates. Under both tVNS and iVNS devices, few and mild adverse effects were reported, and significant improvements in the quality of life were detected. No difference was observed in terms of their impact on mood or concentration. Conclusion Both tVNS and iVNS were found to be a viable and well-tolerated add-on treatment for patients with drug-resistant epilepsy. Both stimulation methods were well tolerated and seemed to be comparably effective in the treatment of epilepsies.

This narrative review examines the growing body of research highlighting the transdiagnostic features of Major Psychoses, encompassing Major Depressive Disorder (MDD), Bipolar Disorder (BD), and Schizophrenia (SZ). Overlapping genetic, psychosocial risk factors, neuroimaging, cognition, course of illness, treatments and psychopathological domains challenge the traditional categorical distinctions that have long defined these disorders. Evidence reveals shared variance in these domains. Furthermore, dimensional approaches, such as the Research Domain Criteria (RDoC), Hierarchical Taxonomy of Psychopathology (HiTOP), network approaches and clinical staging, offer frameworks for understanding these disorders along a continuum rather than within rigid categorical boundaries. This review synthesizes current empirical findings across these domains and emphasizes the need for a re-evaluation of psychiatric classification systems. It argues that a transdiagnostic approach may lead to more explained variance in clinical and neurobiological research, personalized as well as effective diagnostic and treatment strategies, ultimately improving patient outcomes.

<bold>Background and Purpose:</bold> Myeloid-derived suppressor cells (MDSCs) play an important role in the pathogenesis of asthma. Recent publications demonstrated that their function can be modulated by different pharmacological approaches. In this study, we focused on the effects of systemically administered prostaglandin E2 receptor 4 (EP4) agonist L-902,688 and pegylated human Arginase-1 on MDSCs in a murine model of chronic asthma and asthma exacerbation. <bold>Experimental Approach:</bold> BALB/c mice were challenged with house dust mite (HDM) over a period of five weeks, establishing a chronic asthma phenotype. To induce asthma exacerbation, mice were infected with Influenza Virus H1N1 A/Puerto Rico/8/1934. In vivo lung function, lung inflammatory features, number and suppressive activity of MDSCs, number of different T cell subsets in lung and spleen and viral titre in the bronchoalveolar lavage fluid (BALF) were assessed. <bold>Key Results:</bold> In asthmatic mice, treatment with EP4 agonist or Arginase-1 significantly reduced the number of eosinophils in the BALF. Both treatments improved lung function and ameliorates airway hyperresponsiveness in asthma exacerbation. Number and suppressive activity of MDSCs in the lung were boosted by virus-induced asthma exacerbation. <bold>Conclusion and Implications:</bold> We found beneficial effects of systemic EP4 agonist and Arginase-1 therapy in murine model of chronic asthma and influenza virus induced asthma exacerbation. Our findings highlight the potential efficacy of EP4 agonists, Arginase-1and MDSCs, as novel therapeutic approaches in asthma and asthma exacerbation.

BackgroundIris neovascularization and vitreous hemorrhages are typical sequels of ischemic retinopathies. Here, we report about a patient who developed marked iris neovascularization without signs of posterior retinal ischemia.Case PresentationA 56-year-old patient developed marked iris neovascularization after surgery for rhegmatogenous retinal detachment due to a giant retinal tear had been performed 40 years earlier. With repeatedly applied intravitreal injections of an anti-VEGF drug being unsuccessful, anterior retinal cryocoagulations with deep indentation by the cryoprobe to somehow touch and coagulate the detached anterior flap of giant tear were carried out. Subsequently, the vitreous hemorrhage cleared without any further intervention, and iris neovascularization subsided. Retinal fluorescein angiogram did not reveal signs of ischemia of the attached central retina.ConclusionMarked iris neovascularization can disappear after applying peripheral retinal cryocoagulation and laser coagulation. It may lead to the question whether neovascular AMD, potentially associated with macular ischemia, might theoretically be addressable by ablative procedures of the peripheral retina.

Abstract As cancer cell specific rewiring of metabolic networks creates potential therapeutic opportunities, we conducted a synthetic lethal screen utilizing inhibitors of metabolic pathways. Simultaneous administration of (R)-GNE-140 and BMS-986205 (Linrodostat) preferentially halted proliferation of ovarian cancer cells, but not of their non-oncogenically transformed progenitor cells. While (R)-GNE-140 inhibits lactate dehydrogenase (LDH)A/B and thus effective glycolysis, BMS-986205, in addition to its known inhibitory activity on Indoleamine 2,3-dioxygenase (IDO1), also restricts oxidative phosphorylation (OXPHOS), as revealed here. BMS-986205, which is being tested in multiple Phase III clinical trials, inhibits the ubiquinone reduction site of respiratory complex I and thus compromises mitochondrial ATP production. The energetic catastrophe caused by simultaneous interference with glycolysis and OXPHOS resulted in either cell death or the induction of senescence in tumor cells, with the latter being eliminated by senolytics. The frequent synergy observed with combined inhibitor treatment was comprehensively confirmed through testing on tumor cell lines from the DepMap panel and on human colorectal cancer organoids. These experiments revealed highly synergistic activity of the compounds in a third of the tested tumor cell lines, correlating with alterations in genes with known roles in metabolic regulation and demonstrating the therapeutic potential of metabolic intervention.