An experimental DUAL model of advanced liver damage

Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol-associated liver disease plus metabolic-associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA-sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets

An ensemble approach for inferring semi-quantitative regulatory dynamics for the differentiation of mouse embryonic stem cells using prior knowledge.

The process of differentiation of embryonic stem cells (ESCs) is currently becoming the focus of many systems biologists not only due to mechanistic interest but also since it is expected to play an increasingly important role in regenerative medicine, in particular with the advert to induced pluripotent stem cells. These ESCs give rise to the formation of the three germ layers and therefore to the formation of all tissues and organs. Here, we present a computational method for inferring regulatory interactions between the genes involved in ESC differentiation based on time resolved microarray profiles. Fully quantitative methods are commonly unavailable on such large-scale data; on the other hand, purely qualitative methods may fail to capture some of the more detailed regulations. Our method combines the beneficial aspects of qualitative and quantitative (ODE-based) modeling approaches searching for quantitative interaction coefficients in a discrete and qualitative state space. We further optimize on an ensemble of networks to detect essential properties and compare networks with respect to robustness. Applied to a toy model our method is able to reconstruct the original network and outperforms an entire discrete boolean approach. In particular, we show that including prior knowledge leads to more accurate results. Applied to data from differentiating mouse ESCs reveals new regulatory interactions, in particular we confirm the activation of Foxh1 through Oct4, mediating Nodal signaling

Flow Injection Systems With Inductively-coupled Argon Plasma Atomic Emission Spectrometry. Part 1. Fundamental Considerations

Flow injection systems with inductively-coupled argon plasma atomic emission spectromeiry are proposed. Effects of flow rates, injected volumes and mixing Coil lengths are investigated and conditions for the measurement of the flow injection transient signal are discussed. The peak profile measured with the spectrometer corresponds well with the estimate of the true sample zone distribution near the inlet of the spectrometer made by a zone-sampling process; thus the plasma is not a limiting factor in the proposed systems. For plant analysis, the system provides nearly zero sample dispersion and so the inherent sensitivity of the spectrometric method is preserved. The results obtained for 10 elements in the NBS Orchard Leaves reference material (SRM 1571) are in good agreement with the certified values. For determinations of calcium and magnesium in dolomitic limestones, cadmium is used as internal standard and so the merging zones configuration is employed. The proposed system provides medium sample dispersion and permits about 100 samples to be analysed per hour. Relative standard deviations of 1.34% and 1.23% were calculated for the calcium and magnesium data, respectively. The analytical results compare favorably with those obtained by normal i.c.p. spectrometry with pneumatic sample aspiration, after manual sample dilution. © 1981.1302243255IEEE,IEEE Power Electronics Society (PELS),IK4 IKERLAN Research Alliance,OPALT-RT Technologies,Plexim - Electrical Engineering SoftwareRůžička, Hansen, (1975) Anal. Chim. Acta, 78, p. 145Růžička, Hansen, (1980) Anal. Chim. Acta, 114, p. 19Růžička, Hansen, (1981) Flow Injection Analysis, , Wiley-Interscience, New YorkZagatto, Krug, Bergamin F, Jørgensen, Reis, (1979) Anal. Chim. Acta, 104, p. 279Bergamin F, Zagatto, Reis, Krug, (1978) Anal. Chim. Acta, 101, p. 17Yoza, Aoyagi, Ohashi, Tateda, (1979) Anal. Chim. Acta, 111, p. 163Basson, van Staden, (1980) Fresenius Z. Anal. Chem., 302, p. 370Reis, Jacintho, Mortatti, Krug, Zagatto, Bergamin F, Pessenda, (1981) Anal. Chim. Acta, 123, p. 221Beasecker, Williams, (1978) Jarrell—Ash Plasma Newsl., 1 (3), p. 5Rutledge, McClurg, (1980) Jarrell—Ash Plasma Newsl., 3 (3), p. 4Růžička, Hansen, (1978) Anal. Chim. Acta, 99, p. 37Stewart, Růžička, (1976) Anal. Chim. Acta, 82, p. 137Bergamin F, Medeiros, Reis, Zagatto, (1978) Anal. Chim. Acta, 101, p. 9Bergamin F, Reis, Jacintho, Zagatto, (1980) Anal. Chim. Acta, 117, p. 81Hansen, Růžička, (1976) Anal. Chim. Acta, 87, p. 353Zagatto, Reis, Bergamin F, Krug, (1979) Anal. Chim. Acta, 109, p. 45Giné, Bergamin F, Zagatto, Reis, (1980) Anal. Chim. Acta, 114, p. 191Reis, Zagatto, Jacintho, Krug, Bergamin F, Merging zones in flow injection analysis (1980) Analytica Chimica Acta, 119, p. 305Krug, Bergamin F, Zagatto, Jørgensen, (1977) Analyst, 102, p. 503Pinta, (1975) Atomic Absorption Spectrometry, p. 146. , Adam Hilger, LondonBradbury, (1978) Jarrell—Ash Plasma Newsl., 1 (2), p. 1Jones, Jr., (1978) Jarrell—Ash Plasma Newsl., 1 (1), p.

Outcomes-Adjusted Reimbursement in a Health-Care Delivery System

This paper considers a health-care delivery system with two noncooperative parties: a purchaser of medical services and a specialized provider. A dynamic principal-agent model that captures the interaction between the two parties is developed. In this model, patients arrive exogenously, receive periodic treatment from the provider, suffer costly complications that require hospital care, and eventually exit the system in death. The provider chooses the intensity of treatment in each period, incurs an associated cost, and is reimbursed by the purchaser according to observed patient outcomes. The purchaser's problem is to determine a payment system that will induce treatment choices maximizing total social welfare. The optimal payment system, referred to as the outcomes-adjusted payment system, is identified. It consists of a prospective payment per patient and a retrospective payment adjustment based on adverse short-term patient outcomes. This system induces the most efficient delivery of medical services by combining the immediate "threat" of a retrospective payment adjustment with the future reward of prospective payments generated by surviving patients. A numerical example is provided in the context of Medicare's End-Stage Renal Disease program. The example compares the optimal system to systems that are currently in place. The results suggest that the purchaser can achieve significant gains in patient life expectancy by switching to the outcomes-adjusted payment system, but this requires accurate information about treatment technology, patient characteristics, and provider preferences. The life-expectancy gains do not involve increased medical expenditures.Health-Care Financing, Fee for Service, Capitation, Principal-Agent Models, Dynamic Incentives, End-Stage Renal Disease