Basal MET phosphorylation is an indicator of hepatocyte dysregulation in liver disease.

Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, metabolic dysfunction-associated steatotic liver disease (MASLD) is gaining importance as the disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in MASLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) an increased basal MET phosphorylation and a strong downregulation of the PI3K-AKT pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.

The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors.

Most lncRNAs display species-specific expression patterns suggesting that animal models of cancer may only incompletely recapitulate the regulatory crosstalk between lncRNAs and oncogenic pathways in humans. Among these pathways, Sonic Hedgehog (SHH) signaling is aberrantly activated in several human cancer entities. We unravel that aberrant expression of the primate-specific lncRNA HedgeHog Interacting Protein-AntiSense 1 (HHIP-AS1) is a hallmark of SHH-driven tumors including medulloblastoma and atypical teratoid/rhabdoid tumors. HHIP-AS1 is actively transcribed from a bidirectional promoter shared with SHH regulator HHIP. Knockdown of HHIP-AS1 induces mitotic spindle deregulation impairing tumorigenicity in vitro and in vivo. Mechanistically, HHIP-AS1 binds directly to the mRNA of cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2) and attenuates its degradation by hsa-miR-425-5p. We uncover that neither HHIP-AS1 nor the corresponding regulatory element in DYNC1I2 are evolutionary conserved in mice. Taken together, we discover an lncRNA-mediated mechanism that enables the pro-mitotic effects of SHH pathway activation in human tumors.

Effectiveness of Medical Rehabilitation on Return-to-Work Depends on the Interplay of Occupation Characteristics and Disease.

Introduction Work disability causes high costs for economy, organizations, and employees. However, medical rehabilitation does not always enable employees to return to their old jobs. In the present study, we investigated how disease classification and work characteristics interact in predicting the success of medical rehabilitation in terms of one's ability to return to a former job. Methods To this end, we matched 2009 patient data from the German Statutory Pension Insurance agency with job characteristics data from the Occupational Information Network (O*NET) 17.0 database. We used a multilevel approach and a sample of N = 72,029, nested in 194 occupational groups. Results We found that workers are less likely to reenter a former job if mental illnesses coincide with emotionally demanding labor and if musculoskeletal diseases coincide with extreme environmental conditions. We did not find different effects between occupational groups for other types of diseases (circulatory system, neoplasms, injuries, others). Conclusion Thus, the contextual overlap of disease and occupational characteristics notably lowers the chances of a successful return-to-work. These findings should be taken into account by physicians when attempting to set realistic goals for rehabilitation in collaboration with the patient and the funding agency.

Categorical interoception: perceptual organization of sensations from inside.

Adequate perception of bodily sensations is essential to protect health. However, misinterpretation of signals from within the body is common and can be fatal, for example, in asthma or cardiovascular disease. We suggest that placing interoceptive stimuli into interoceptive categories (e.g., the category of symptoms vs. the category of benign sensations) leads to perceptual generalization effects that may underlie misinterpretation. In two studies, we presented stimuli inducing respiratory effort (respiratory loads) either organized into categories or located on a continuous dimension. We found pervasive effects of categorization on magnitude estimations, affective stimulus evaluations, stimulus recognition, and breathing behavior. These findings indicate the need for broadening perspectives on interoception to include basal processes of stimulus organization, in order for interoceptive bias to be understood. The results are relevant to a wide range of interoception-related phenomena, from emotion to symptom perception.