Citations

Elucidating the structure and function of enteropeptidase (EP) is essential for advancing our understanding of its biological significance, particularly in regulating trypsinogen activation. Using cryo-EM and enzymatic activity, we uncovered the significance of the CUB2 domain in mediating the cleavage of macromolecular substrates. We identified crucial binding loops and key residues for EP’s proteolytic function. The mutation E574A enhanced the proteolytic activity of EP, whereas the mutation N619A diminished its cleavage efficiency, highlighting the importance of surface-charged interactions in modulating EP’s activity. A proteolytic cycle was proposed to deepen our understanding of the trypsinogen activation by EP. This work offers valuable insights into the molecular mechanisms underlying EP’s interaction with its substrate, and opens up avenues for therapeutically modulating EP-mediated proteolysis.

Abstract Background Neurofibromatosis type 1 (NF1) is a multisystem genetic condition. Up to 50% of individuals with NF1 develop plexiform neurofibromas (PN) that can cause pain and significant morbidity, impairing quality of life. As of December 2025, only a limited number of countries have an approved medical treatment for adults with NF1-PN. A systematic literature review (PROSPERO CRD42023463980) was conducted to better understand disease burden and unmet need in this population. Methods An evidence prioritization strategy identified studies reporting on NF1-PN populations with ≥50% adults from database searches conducted between 1988 and July 20, 2023. Studies published in the last 15 years were extracted. Results Of 3242 identified sources, 57 publications (53 unique studies) were included. The proportion of adults with NF1 who had PN ranged from 11.8% to 84.9% (n = 9 studies). Annual median change in untreated PN volume was −3.7% to +8.3% (n = 5 articles). Pain was the most common PN-related manifestation (32.0%–38.4% of patients; n = 12 articles). Malignant PN transformation occurred in 2.0%–4.1% of patients (n = 5 cohorts); 3 shorter-term studies reported no transformation. Surgery was performed in 69.5% of patients (n = 7 cohorts); post-operative complications occurred in 13.0%–30.0% (n = 3 articles). Analgesia was the most reported pharmacological treatment (37.9% of patients; n = 7 articles). Limited data indicated that PN monitoring and surgery cause substantial resource use. No studies reported on caregiver burden, healthcare costs, or transition from pediatric to adult care. Conclusions Adults with NF1-PN experience high disease burden. Data gaps exist for epidemiology, transition of care, caregiver burden, healthcare cost, and resource use.

Introduction: Spontaneous coronary artery dissection (SCAD) is an understudied cause of acute myocardial infarction due to hematoma formation in coronary arteries primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Methods and Results: Through a meta-analysis of 8 GWAS (1917 cases, 9292 controls of European ancestry), we identified 17 risk loci, including 12 new. Functional annotations pointed at enrichment in enhancer marks of arteries, specifically smooth muscle cells, and strong candidate genes, such as tissue factor gene ( F3 ) on Chr1 near rs1146473 (OR=1.32, P=5.8 х10 -9 ). F3 is novel for SCAD or any cardiovascular disease. The risk allele correlated with F3 lower expression in arteries, supporting a mechanism consistent with hematoma formation. Bayesian gene regulatory networks constructed from expression and genetics data indicated the extracellular matrix organization in arteries as the biological function where most prioritized genes clustered (e.g. COL4A1/A2, HTRA1, and TIMP3 ). Overall, we report substantial polygenicity for SCAD (LDSC: h 2 SNP = 0.71 ± 0.11) and shared genetics with several neurovascular diseases (e.g intracranial aneurysm). Intriguingly, for 6 loci, colocalization analyses showed that SCAD and CAD are likely to share the same causal variants but involve opposite risk alleles (e.g COL4A1/A2 ). In addition, a negative genetic correlation was found between SCAD and CAD (rg=-0.12; P=3.7х10 -3 ), including after conditioning on BP (mt-COJO: rg CAD/SBP =-0.19, P=4.6х10 -6 ). Mendelian randomization analyses indicated higher BP to associate with increased risk for SCAD (beta IVW-SBP =0.05, P=7.6х10 -6 , beta IVW-DBP =0.10, P=1.9х10 -6 ) and CAD (beta IVW-SBP =0.04, P=8.6х10 -49 ; DBP: beta IVW-DBP =0.06, P=1.6х10 -44 ) but not BMI, lipids, or type 2 diabetes, which we confirmed as genetic risk factors for CAD Conclusions: Our results set the stage for future investigation of novel biological pathways relevant to both SCAD and CAD and potential therapeutic and preventive strategies specifically targeting this ischemic disease predominantly affecting women.

The signaling molecule adenosine has been implicated in attenuating acute lung injury (ALI). Adenosine signaling is terminated by its uptake through equilibrative nucleoside transporters (ENTs). We hypothesized that ENT‐dependent adenosine uptake could be targeted to enhance adenosine‐mediated lung protection. To address this hypothesis, we exposed mice to high‐pressure mechanical ventilation to induce ALI. Initial studies demonstrated time‐dependent repression of ENT1 and ENT2 transcript and protein levels during ALI. To examine the contention that ENT repression represents an endogenous adaptive response, we performed functional studies with the ENT inhibitor dipyridamole. Dipyridamole treatment (1 mg/kg; EC 50 =10 μM) was associated with significant increases in ALI survival time (277 vs. 395 min; P <0.05). Subsequent studies in gene‐targeted mice for Ent1 or Ent2 revealed a selective phenotype in Ent2 ‐/‐ mice, including attenuated pulmonary edema and improved gas exchange during ALI in conjunction with elevated adenosine levels in the bronchoalveolar fluid. Furthermore, studies in genetic models for adenosine receptors implicated the A 2B adenosine receptor (Adora2b) in mediating ENT‐dependent lung protection. Notably, dipyridamole‐dependent attenuation of lung inflammation was abolished in mice with alveolar epithelial Adora2b gene deletion. Our newly identified crosstalk pathway between ENT2 and alveolar epithelial Adora2b in lung protection during ALI opens possibilities for combined therapies targeted to this protein set.—Eckle, T., Hughes, K., Ehrentraut, H., Brodsky, K. S., Rosenberger, P., Choi, D.‐S., Ravid, K., Weng, T., Xia, Y., Blackburn, M. R.Eltzschig, H. K., Crosstalk between the equilibrative nucleoside transporter ENT2 and alveolar Adora2b adenosine receptors dampens acute lung injury. FASEB J. 27, 3078–3089 (2013). www.fasebj.org