Background/Aims: MicroRNA (miRNA) isoforms (isomiRs) broaden the regulatory landscape of canonical miRNAs, but their role in metabolic dysfunction-associated steatotic liver disease (MASLD) remains unknown. We aimed to characterize the hepatic isomiR landscape in MASLD and define their association with disease activity and fibrosis. Methods: Small RNA (sRNA) sequencing was performed on liver biopsies from 79 patients across the histological spectrum of MASLD. IsomiRs were annotated and quantified. Their association to disease activity and fibrosis score was assessed by differential expression, ordinal regression, and machine learning. Parallel mRNA sequencing and pathway enrichment were used to map isomiR–mRNA interactions and regulatory networks, which were validated against an independent dataset. Results: MiRNAs accounted for 75% of sRNAs in liver tissue, of which 67% were isomiRs. Across MASLD severity, 173 isomiRs correlated with disease activity and 58 with fibrosis stage. Key findings included a miR-122 isomiR uniquely targeting INSIG1 (cholesterol metabolism) and a miR-21 isomiR targeting PPARA and HMGCS2 (lipid and fibrosis pathways). Integration with mRNA data revealed 33 dysregulated pathways, including PPAR signaling, insulin resistance, and TGF-β response. Several novel isomiRs from miR-26b, let-7c, and miR-32 families were also linked to lipid metabolism and fibrosis progression. Conclusions IsomiRs represent the majority of hepatic miRNAs and uncover novel regulatory networks masked by canonical miRNA analysis. These findings provide new insights into the molecular heterogeneity of MASLD, highlight candidate pathways driving disease progression, and identify potential biomarkers and therapeutic targets for precision hepatology.

Methods: This retrospective study was performed on degenerative cervical myelopathy patients with a complete composite grip strength assessment between January 2013 to January 2019. The Biometrics E-link hand kit was used for the assessment. The following parameters were measured: maximum grip strength, sustained grip strength, three-jaw pinch, maximum key pinch, and sustained key pinch. The pre- and postoperative functional status was assessed using the Nurick grade and the modified Japanese Orthopaedic Association (mJOA) score. Results: A total of 40 patients were included in the study. The mean patient age was 51.9 years. The mean preoperative Nurick grade was 3.5 and the mJOA score was 10.9. The anterior approach was used in 25 patients, and the posterior approach was used in 15 patients. Four patients developed complications. Degenerative cervical myelopathy resulted in decreased handgrip and pinch strength as compared to normative Indian data. There was a significant improvement in the postoperative composite grip strength for all five parameters. There was no differential improvement between the anterior and posterior surgical groups. The improvement in the composite grip strength correlated with the improvement in functional scores. Conclusions Composite grip strength analysis is an objective method for assessing the impact of degenerative cervical myelopathy on grip strength and monitoring the postoperative improvement. Decompressive surgery resulted in global improvement in all the parameters of composite grip strength.

Fatty acid synthase (FASN, EC 2.3.1.85), is a multi-enzyme dimer complex that plays a critical role in lipogenesis. This lipogenic enzyme has gained importance beyond its physiological role due to its implications in several clinical conditions-cancers, obesity, and diabetes. This has made FASN an attractive pharmacological target. Here, we have attempted to predict the theoretical models for the human enoyl reductase (ER) and beta-ketoacyl reductase (KR) domains based on the porcine FASN crystal structure, which was the structurally closest template available at the time of this study. Comparative modeling methods were used for studying the structure-function relationships. Different validation studies revealed the predicted structures to be highly plausible. The respective substrates of ER and KR domains-namely, trans-butenoyl and beta-ketobutyryl-were computationally docked into active sites using Glide in order to understand the probable binding mode. The molecular dynamics simulations of the apo and holo states of ER and KR showed stable backbone root mean square deviation trajectories with minimal deviation. Ramachandran plot analysis showed 96.0% of residues in the most favorable region for ER and 90.3% for the KR domain, respectively. Thus, the predicted models yielded significant insights into the substrate binding modes of the ER and KR catalytic domains and will aid in identifying novel chemical inhibitors of human FASN that target these domains.
Catalytic Domain* ; Humans ; Lipogenesis ; Models, Theoretical ; Molecular Dynamics Simulation* ; Obesity ; Oxidoreductases*