Pancreatic adaptive responses in alcohol abuse: Role of the unfolded protein response.

The majority of those who drink excessive amounts of alcohol do not develop pancreatic disease. One overarching hypothesis is that alcohol abuse requires additional risk factors, either environmental or genetic, for disease to occur. However, another reason be a result of alcohol-induced activation of adaptive systems that protect the pancreas from the toxic effects of alcohol. We show that mechanisms within the unfolded protein response (UPR) of the endoplasmic reticulum (ER) that can lead to protection of the pancreas from pancreatic diseases with alcohol abuse. The remarkable ability of the pancreas to adapt its machinery to alcohol abuse using UPR systems and continue functioning is the likely reason that pancreatitis from alcohol abuse does not occur in the majority of heavy drinkers. These findings indicate that methods to enhance the protective responses of the UPR can provide opportunities for prevention and treatment of pancreatic diseases

Determination of Rottlerin, a Natural Protein Kinases C Inhibitor, in Pancreatic Cancer Cells and Mouse Xenografts by RP-HPLC Method.

Rottlerin is a natural polyphenolic ketone isolated from the pericarps of Mallotus phillippinensis. In previous studies we showed that parenteral administration of rottlerin reduced tumor growth in murine xenograft models of pancreatic cancer. The aim of this study was to develop a simple and validated method for the quantitative determination of rottlerin in plasma and tumor tissues of mice fed a rottlerin diet. A xenograft model of pancreatic cancer was prepared by injection of 2×106 HPAF-II cells subcutaneously into nude mice. One week before tumor implantation, mice were randomly allocated to standard diet (AIN76A) and standard diet supplement with 0.012% rottlerin (n=6 per group). Mice were sacrificed after 6 weeks on diets. Rottlerin was extracted from the plasma and tissues using protein precipitation-extraction and analyzed by reverse-phase HPLC-DAD method. The same HPLC method was also applied to determine rottlerin levels in conditioned culture media and in cell lysates from HPAF-II cells exposed to 25 µM concentration of rottlerin. A substantial amount of rottlerin was detected in tumor (2.11 ± 0.25 nmol/g tissue) and plasma (2.88 ± 0.41 µM) in mice fed rottlerin diet. In addition, significant levels of rottlerin (57.4 ± 5.4 nmol/mg protein) were detected in cell lysates from rottlerin-treated HPAF-II cells. These data indicate that rottlerin is efficiently absorbed in cells and tissues both in vivo and in vitro and suggest a strong potential for rottlerin as a preventive or adjuvant supplement for pancreatic cancer

Sometimers, Alzheimer’s? I love That! That’s definitely me”: Readers’ Responses to Fictional Dementia Narratives

https://gtr.ukri.org/projects?ref=AH%2FS001476%2F1This article presents findings from an interdisciplinary project which invited readers to experience the impact of dementia via fictional characters’ narratives. Combining methods from critical gerontology and literary linguistics—a field that examines the language of literature—we undertook an empirical reader response study of dementia fiction. We constructed a large corpus of dementia fiction; selecting 12 extracts, each containing first-hand, focalized accounts of fictional characters’ experiences of living with dementia. Readers (31) were purposively sampled for 4 separate reading groups—student social workers (9); general public (9); family carers (6); and people with dementia (7). Over 6 weeks they engaged in separate, facilitated, on-line group discussions of extracts. Discussions were independently coded using ATLAS.ti. Although readers from all 4 groups reported that fictional characters drew them into the internal life of someone with dementia, some carers questioned whether fictional characters’ experiences were plausible. Readers with dementia recognized themselves in the extracts; viewing fictional characters as eloquent envoys of their lived experiences of diagnosis, social isolation, loss of language, and use of humor. Fictional characters offer an entry point for understanding contrasts in caregiver and care-receiver experiences of dementia. Fictional characters are potentially useful for moving dementia narratives beyond monstrous cultural metaphors and onto a disability-based rights agenda.Arts and Humanities Research Council (grant number AH/S001476/1

The visualisation of cognitive structures in forensic statements

Forensic statements are often unstructured, intricate, and thus difficult to interpret and assess. This is due to the varied nature and format of how interviews with victims, witnesses, or suspects are conducted. It is even more difficult for police investigators, lawyers or other legal practitioners to grasp intuitively and accurately the key information pertaining within the varied statements. This research investigates the opportunities in the convergence of linguistic approaches to extracting and reconstructing the cognitive structure, i.e. “Text-Worlds”, in a statement, and the computerised operational settings for enabling effective and hopefully more accurate interpretation of forensic discourse through visualisation

The Differential Role of Human Cationic Trypsinogen (PRSS1) p.R122H Mutation in Hereditary and Nonhereditary Chronic Pancreatitis: A Systematic Review and Meta-Analysis.

Background:Environmental factors and genetic mutations have been increasingly recognized as risk factors for chronic pancreatitis (CP). The PRSS1 p.R122H mutation was the first discovered to affect hereditary CP, with 80% penetrance. We performed here a systematic review and meta-analysis to evaluate the associations of PRSS1 p.R122H mutation with CP of diverse etiology. Methods:The PubMed, EMBASE, and MEDLINE database were reviewed. The pooled odds ratio (OR) with 95% confidence intervals was used to evaluate the association of p.R122H mutation with CP. Initial analysis was conducted with all etiologies of CP, followed by a subgroup analysis for hereditary and nonhereditary CP, including alcoholic or idiopathic CP. Results:A total of eight case-control studies (1733 cases and 2415 controls) were identified and included. Overall, PRSS1 p.R122H mutation was significantly associated with an increased risk of CP (OR = 4.78[1.13-20.20]). Further analysis showed p.R122H mutation strongly associated with the increased risk of hereditary CP (OR = 65.52[9.09-472.48]) but not with nonhereditary CP, both alcoholic and idiopathic CP. Conclusions:Our study showing the differential role of p.R122H mutation in various etiologies of CP indicates that this complex disorder is likely influenced by multiple genetic factors as well as environmental factors

Projecting uncertainty: Visualising text-worlds in three statements from the Meredith Kercher murder case

This article uses Text World Theory (Werth 1999; Gavins 2007) in conjunction with VUE (Visual Understanding Environment) concept mapping software to analyze three statements from the trial of Amanda Knox, convicted in 2009 of the murder of Meredith Kercher. We compare the cognitive structures of the statements and use the insights gained to guide an examination of their individual linguistic features and associated potential interpretative effects. In the first two dictated statements, Knox is projected as an actor responsible for the reported actions/events that implicate her in the crime, whereas in the third statement (hand-written in English), she is projected as a sensor, presenting more prominent epistemic uncertainty and indicating bewilderment. We argue that using VUE diagramming software extends the scope of Text World Theory, by increasing its capacity for managing analytically lengthy and complex datasets

A Visualization Method for Understanding Forensic Statements

Forensic statements are lengthy and contain large amounts of complex information. Consequently, it is often difficult for readers of such reports to identify connections between disparate pieces of evidence and to properly and objectively assess their value to the case in question. Readers have no alternative but to rely on intuition and experience to make sense of the complex arguments and propositions arising from forensic evidence. This research investigates the opportunities in the convergence of linguistic approaches to extracting and reconstructing the cognitive structure, i.e. “TextWorlds”, in a statement, and the computerized operational settings for enabling effective and hopefully more accurate interpretation of forensic discourse through visualization. This will be of benefit to a wide range of stakeholders, including investigating officers, prosecuting and defence counsels, judges and jurors

Ethanol Induced Disordering of Pancreatic Acinar Cell Endoplasmic Reticulum: An ER Stress/Defective Unfolded Protein Response Model.

Background & aimsHeavy alcohol drinking is associated with pancreatitis, whereas moderate intake lowers the risk. Mice fed ethanol long term show no pancreas damage unless adaptive/protective responses mediating proteostasis are disrupted. Pancreatic acini synthesize digestive enzymes (largely serine hydrolases) in the endoplasmic reticulum (ER), where perturbations (eg, alcohol consumption) activate adaptive unfolded protein responses orchestrated by spliced X-box binding protein 1 (XBP1). Here, we examined ethanol-induced early structural changes in pancreatic ER proteins.MethodsWild-type and Xbp1+/- mice were fed control and ethanol diets, then tissues were homogenized and fractionated. ER proteins were labeled with a cysteine-reactive probe, isotope-coded affinity tag to obtain a novel pancreatic redox ER proteome. Specific labeling of active serine hydrolases in ER with fluorophosphonate desthiobiotin also was characterized proteomically. Protein structural perturbation by redox changes was evaluated further in molecular dynamic simulations.ResultsEthanol feeding and Xbp1 genetic inhibition altered ER redox balance and destabilized key proteins. Proteomic data and molecular dynamic simulations of Carboxyl ester lipase (Cel), a unique serine hydrolase active within ER, showed an uncoupled disulfide bond involving Cel Cys266, Cel dimerization, ER retention, and complex formation in ethanol-fed, XBP1-deficient mice.ConclusionsResults documented in ethanol-fed mice lacking sufficient spliced XBP1 illustrate consequences of ER stress extended by preventing unfolded protein response from fully restoring pancreatic acinar cell proteostasis during ethanol-induced redox challenge. In this model, orderly protein folding and transport to the secretory pathway were disrupted, and abundant molecules including Cel with perturbed structures were retained in ER, promoting ER stress-related pancreas pathology