8 research outputs found
Fuzzy systems and neural networks XML schemas for soft computing
This article presents an XML[2] based language for the specification of objects in the Soft Computing area. The design promotes reuse and takes a compositional approach in which more complex constructs are built from simpler ones; it is also independent of implementation details as the definition of the language only states the expected behaviour of every possible implementation. Here the basic structures for the specification of concepts in the Fuzzy Logic area are described and a simple construct for a generic neural network model is introduced
Beneficial Effect of Ursodeoxycholic Acid in Patients with ACOX2 Deficiency-Associated Hypertransaminasemia
Background: A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27-BAs, mainly trihydroxycholestanoic acid (THCA).
Aims: To investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration.
Methods & results: Among 33 patients with unexplained hypertransaminasemia from 11 hospitals, and 13 of their relatives, 7 individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by HPLC-MS/MS. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in 2 patients and 3 family members. Two additional non-related patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In ADAH patients, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized transaminases levels. Incubation of HuH-7 liver cells with THCA, which was efficiently taken up, but not through BA transporters, increased ROS production (flow cytometry), ER stress biomarkers (GRP78, CHOP and XBP1-S/XBP1-U ratio), and BAX¿ expression (RT-qPCR and immunoblot), whereas cell viability was decreased (MTT). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site-directed mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH.
Conclusion: Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a non-invasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.This study was supported by the following
grants: CIBERehd (EHD15PI05/2016);
Fondo de Investigaciones Sanitarias,
Instituto de Salud Carlos III, Spain
(PI19/00819 and PI20/00189), co-funded
by European Regional Development
Fund/European Social Fund, “Investing
in your future”; “Junta de Castilla y León”
(SA074P20); Fundació Marato TV3
(201916–31);
AECC Scientific Foundation
(2017/2020), Spain; and “Centro
Internacional sobre el Envejecimiento”
(OLD-HEPAMARKER,
0348_CIE_6_E),
Spain. We also acknowledge support
from grants PID2019-111669RBI-
100,
PID2020-115055RB-
I00
from Plan
Nacional de I+D funded by the “Agencia
Estatal de Investigación” (AEI) and the
center grant P50AA011999 Southern
California Research Center for ALPD
and Cirrhosis funded by NIAAA/NIH,
as well as support from AGAUR of
the “Generalitat de Catalunya” SGR-2017-
1112,
European Cooperation in
Science & Technology (COST) ACTION
CA17112 Prospective European Drug-Induced
Liver Injury Network. Marta
Alonso-Peña
was the recipient of a
predoctoral fellowship from “Ministerio de
Educación, Cultura y Deporte” (BOE-A-
2015-
9456;
FPU-14/
00214) and a Mobility
Grant for Short Stays from “Ministerio
de Ciencia, Innovación y Universidades”
(EST17/00186). Ricardo Espinosa-Escudero
is the recipient of a predoctoral
fellowship from “Junta de Castilla y
León” and “Fondo Social Europeo”
(EDU/574/2018). The funding sources
were not involved in the research design
or preparation of the articl
Fuzzy systems and neural networks XML schemas for soft computing
This article presents an XML[2] based language for the specification of objects in the Soft Computing area. The design promotes reuse and takes a compositional approach in which more complex constructs are built from simpler ones; it is also independent of implementation details as the definition of the language only states the expected behaviour of every possible implementation. Here the basic structures for the specification of concepts in the Fuzzy Logic area are described and a simple construct for a generic neural network model is introduced