FTY720/fingolimod decreases hepatic steatosis and expression of fatty acid synthase in diet-induced nonalcoholic fatty liver disease in mice

Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver dysfunction, is a metabolic disease that begins with steatosis. Sphingolipid metabolites, particularly ceramide and sphingosine-1-phosphate (S1P), have recently received attention for their potential roles in insulin resistance and hepatic steatosis. FTY720/fingolimod, a prodrug for the treatment of multiple sclerosis, is phosphorylated in vivo to its active phosphorylated form by sphingosine kinase 2 and has been shown to interfere with the actions of S1P and to inhibit ceramide biosynthesis. Therefore, in this study we investigated the effects of FTY720 in a diet-induced animal model of NAFLD (DIAMOND) that recapitulates the hallmarks of the human disease. The oral administration of FTY720 to these mice fed a high-fat diet and sugar water improved glucose tolerance and reduced steatosis. In addition to decreasing liver triglycerides, FTY720 also reduced hepatic sphingolipid levels, including ceramides, monohexosylceramides, and sphingomyelins, particularly the C16:0 and C24:1 species, as well as S1P and dihydro-S1P. FTY720 administration decreased diet-induced fatty acid synthase (FASN) expression in DIAMOND mice without affecting other key enzymes in lipogenesis. FTY720 had no effect on the expression of SREBP-1c, which transcriptionally activates FASN. However, in agreement with the notion that the active phosphorylated form of FTY720 is an inhibitor of histone deacetylases, FTY720-P accumulated in the liver, and histone H3K9 acetylation was markedly increased in these mice. Hence, FTY720 might be useful for attenuating FASN expression and triglyceride accumulation associated with steatosis. Keywords: lipogenesis; sphingolipids; sphingosine-1-phosphate

An evaluation of three DoE-guided meta-heuristic-based solution methods for a three-echelon sustainable distribution network

This article evaluates the efficiency of three meta-heuristic optimiser (viz. MOGA-II, MOPSO and NSGA-II)-based solution methods for designing a sustainable three-echelon distribution network. The distribution network employs a bi-objective location-routing model. Due to the mathematically NP-hard nature of the model a multi-disciplinary optimisation commercial platform, modeFRONTIER®, is adopted to utilise the solution methods. The proposed Design of Experiment (DoE)-guided solution methods are of two phased that solve the NP-hard model to attain minimal total costs and total CO2 emission from transportation. Convergence of the optimisers are tested and compared. Ranking of the realistic results are examined using Pareto frontiers and the Technique for Order Preference by Similarity to Ideal Solution approach, followed by determination of the optimal transportation routes. A case of an Irish dairy processing industry’s three-echelon logistics network is considered to validate the solution methods. The results obtained through the proposed methods provide information on open/closed distribution centres (DCs), vehicle routing patterns connecting plants to DCs, open DCs to retailers and retailers to retailers, and number of trucks required in each route to transport the products. It is found that the DoE-guided NSGA-II optimiser based solution is more efficient when compared with the DoE-guided MOGA-II and MOPSO optimiser based solution methods in solving the bi-objective NP-hard three-echelon sustainable model. This efficient solution method enable managers to structure the physical distribution network on the demand side of a logistics network, minimising total cost and total CO2 emission from transportation while satisfying all operational constraints

Haptoglobin 2 Allele is Associated With Histologic Response to Vitamin E in Subjects With Nonalcoholic Steatohepatitis

Background: Haptoglobin (Hp) genotype has been linked to oxidative stress and response to vitamin E (VitE) in patients with dyslipidemia. Its effect on histological response to VitE in nonalcoholic steatohepatitis (NASH) is unknown. Goals: Our objective was to determine if Hp genotype associates with response to VitE in patients with NASH. Study: A post hoc analysis of 228 patients receiving VitE or placebo in two clinical trials was performed. Regression analysis was used to assess the effect of VitE versus placebo, by Hp genotype (1–1, 2–1, or 2–2), on histologic features and laboratory markers of liver disease, comparing baseline to end of treatment values. An interaction term was included in the regression models to assess differential treatment effect across Hp genotype. Results: Hp 2–2 patients treated with VitE versus placebo showed significant histologic improvement (51% versus 20%, OR=4·2, p=0·006), resolution of steatohepatitis (44% versus 12%, OR=6.2, p=0·009), decrease in NAFLD Activity Score (NAS) (−2·2 versus −0·6, p=0·001), and decrease in liver enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and γ-glutamyl transpeptidase. Hp 2–1 patients on VitE versus placebo showed improved resolution of steatohepatitis, NAS and liver enzymes. Hp 1–1 patients showed no significant improvement in histology or liver enzymes. VitE had no effect on fibrosis stage in any group. Regression analysis showed incremental benefit of having Hp 2–2 or 2–1 versus 1–1 for all liver enzymes. Conclusion: Hp 2 allele is associated with greater histological and biological improvement in NASH with VitE treatment compared to the Hp 1 allele

Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease

Importance Metabolic dysfunction–associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis.Objective To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)–based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD.Design, Setting, and Participants This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE).Main Outcomes and Measures The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests.Results A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group.Conclusions and Relevance Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis

Targets of the Entamoeba histolytica Transcription Factor URE3-BP

The Entamoeba histolytica transcription factor Upstream Regulatory Element 3-Binding Protein (URE3-BP) is a calcium-responsive regulator of two E. histolytica virulence genes, hgl5 and fdx1. URE3-BP was previously identified by a yeast one-hybrid screen of E. histolytica proteins capable of binding to the sequence TATTCTATT (Upstream Regulatory Element 3 (URE3)) in the promoter regions of hgl5 and fdx1. In this work, precise definition of the consensus URE3 element was performed by electrophoretic mobility shift assays (EMSA) using base-substituted oligonucleotides, and the consensus motif validated using episomal reporter constructs. Transcriptome profiling of a strain induced to produce a dominant-positive URE3-BP was then used to identify additional genes regulated by URE3-BP. Fifty modulated transcripts were identified, and of these the EMSA defined motif T[atg]T[tc][cg]T[at][tgc][tg] was found in over half of the promoters (54% p<0.0001). Fifteen of the URE3-BP regulated genes were potential membrane proteins, suggesting that one function of URE3-BP is to remodel the surface of E. histolytica in response to a calcium signal. Induction of URE3-BP leads to an increase in tranwell migration, suggesting a possible role in the regulation of cellular motility

Species-Specific Immunity Induced by Infection with Entamoeba histolytica and Entamoeba moshkovskii in Mice

Entamoeba histolytica, the parasitic amoeba responsible for amoebiasis, causes approximately 100,000 deaths every year. There is currently no vaccine against this parasite. We have previously shown that intracecal inoculation of E. histolytica trophozoites leads to chronic and non-healing cecitis in mice. Entamoeba moshkovskii, a closely related amoeba, also causes diarrhea and other intestinal disorders in this model. Here, we investigated the effect of infection followed by drug-cure of these species on the induction of immunity against homologous or heterologous species challenge. Mice were infected with E. histolytica or E. moshkovskii and treated with metronidazole 14 days later. Re-challenge with E. histolytica or E. moshkovskii was conducted seven or 28 days following confirmation of the clearance of amoebae, and the degree of protection compared to non-exposed control mice was evaluated. We show that primary infection with these amoebae induces a species-specific immune response which protects against challenge with the homologous, but not a heterologous species. These findings pave the way, therefore, for the identification of novel amoebae antigens that may become the targets of vaccines and provide a useful platform to investigate host protective immunity to Entamoeba infections

Enterocolitis necrotizante en recién nacidos ingresados en el Servicio de Neonatología del Hospital Escuela "Carlos Roberto Huembes" en el período comprendido de Enero 2011 a Diciembre 2013

La enterocolitis necrotizante en el recién nacido presenta un amplio espectro de manifestaciones clínicas, caracterizándose principalmente por la tríada de distensión abdominal, sangramiento gastrointestinal y neumatosis intestinal. A pesar del avance en el cuidado intensivo neonatal, persiste como una enfermedad grave, que afecta habitualmente al recién nacido pretérmino, especialmente de muy bajo peso

Reading between the Lines

In the experience of contemporary cities, urban residents distinguish some locations as labyrinthine and mazelike, familiar and disorienting, mysterious and adventurous. This research focuses on reproduction of such an experiment by mapping the infrastructural lines which connect Essen and Gelsenkirchen in Ruhrgebiet. Therefore more than just a ribbon, the connection line supposes to be a place for a multi-dimensional spatial experiment which creates a complex labyrinth as a new spatial state in the bordering conditions of the city. ‘Reading between the Lines’ is a thematic exploration of architecture which naturally deals concurrently with symbolic and practical aspect. In this approach, the building is not only a shelter to secure or an enclosure of functions, but is a place of connotation, substance, resource and typology. Moreover, referring to architecture as an interdisciplinary act, this project is working with several media such as photography, drawings, models and rendering. The architectural theory, to create the real space, is constantly explored in painting, sculpture, film, poetry, etc. Accordingly, in this project, the traditional sequence ‘program plus site equals form’ is intentionally inverted. So in every single step of the process the outcome of the previous step is interpreted by various methods. At the first step, some superimposed drawings, so called the final mappings, are produced which illustrate the labyrinthine spatial quality of the spaces of the lines such as ‘wandering and errors, passes and impasses, luminous breakaways and tragic seclusion’. As the second phase is a model scale based on interpretation from one final superimposed drawing result in a composition of volumes, surfaces and elements. As the final step, to develop real architectural spaces, a large number of possible orders of the fragments could be represented. Since the project is site less, thus no geographic limitation is considered. Therefore, there are infinite possible orders of the fragments without any spatial coherence. So, all the fragments become autonomous entities. In addition, focusing on specific themes and developing each fragment based on, leads spaces to be varied in scale, materiality and atmospheric experience. To distinct the heterogeneous spaces, each earn a particular name: Space of Wandering, The Wall (Space of Passage), The Tower (Space of Seclusion), etc. Various techniques of representation have been applied to narrate characteristics of these spaces vividly. Furthermore, within a series of fragments, that eventually generates its own context, understanding of scale is left to imagination of the reader, from one item to another, from mega structure to a cabin size room for one.Studio Border ConditionsArchitectureArchitectur