Arginine Depletion Attenuates Renal Cystogenesis in Tuberous Sclerosis Complex Model

Cystic kidney disease is a leading cause of morbidity in patients with tuberous sclerosis complex (TSC). We characterize the misregulated metabolic pathways using cell lines, a TSC mouse model, and human kidney sections. Our study reveals a substantial perturbation in the arginine biosynthesis pathway in TSC models with overexpression of argininosuccinate synthetase 1 (ASS1). The rise in ASS1 expression is dependent on the mechanistic target of rapamycin complex 1 (mTORC1) activity. Arginine depletion prevents mTORC1 hyperactivation and cell cycle progression and averts cystogenic signaling overexpression of c-Myc and P65. Accordingly, an arginine-depleted diet substantially reduces the TSC cystic load in mice, indicating the potential therapeutic effects of arginine deprivation for the treatment of TSC-associated kidney disease

Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy

Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder

Fetal Urine Production Rate in Preterm Premature Rupture of Membranes Is Associated with Adverse Neonatal Outcome: A Pilot Study

Introduction In this study we evaluated the associations between fetal urinary production rate (FUPR), measured by ultrasound, and adverse neonatal outcome in women with preterm premature rupture of membranes (PPROM). Material and Methods We conducted a prospective cohort of singleton pregnancies complicated by PPROM occurring at gestational week 24 or later in a single center. Women with PPROM and conservative management until spontaneous labor (after 48 hours of admission), chorioamnionitis, or induction by protocol at 35+0 weeks. FUPR was evaluated by 2D sonography at admission, and corrected for gestational age. Attending physicians were blinded to FUPR results. The main neonatal outcome measures were chorioamnionitis, placental inflammatory grading, first neonatal creatinine value, first neonatal dextrose value, length of neonatal intensive care unit (NICU) stay, necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH) (grades I-IV), blood transfusions, reduced neonatal urine production rate ( Results The study included 38 women. Low FUPR was associated with chorioamnionitis, longer NICU hospitalization (p=0.01), and higher rates of NEC or IVH (p=0.008), and blood transfusion (p=0.004). There were no significant associations between antenatal FUPR and placental histologic inflammation grading, neonatal creatinine, neonatal dextrose, or early neonatal sepsis. IL-6 levels did not correlate with chorioamnionitis, FUPR, or early sepsis. Conclusion A finding of FUPR on in utero ultrasound examination in pregnancies complicated by PPROM may be indicative of an inflammatory process and predictive of adverse neonatal outcome.</p