Direct transfer of viral and cellular proteins from varicella-zoster virus-infected non-neuronal cells to human axons

10.1371/journal.pone.0126081PLoS ONE105e012608

SIRT6 Promotes Hepatic Beta-Oxidation via Activation of PPARα

The pro-longevity enzyme SIRT6 regulates various metabolic pathways. Gene expression analyses in SIRT6 heterozygotic mice identify significant decreases in PPARα signaling, known to regulate multiple metabolic pathways. SIRT6 binds PPARα and its response element within promoter regions and activates gene transcription. Sirt6+/− results in significantly reduced PPARα-induced β-oxidation and its metabolites and reduced alanine and lactate levels, while inducing pyruvate oxidation. Reciprocally, starved SIRT6 transgenic mice show increased pyruvate, acetylcarnitine, and glycerol levels and significantly induce β-oxidation genes in a PPARα-dependent manner. Furthermore, SIRT6 mediates PPARα inhibition of SREBP-dependent cholesterol and triglyceride synthesis. Mechanistically, SIRT6 binds PPARα coactivator NCOA2 and decreases liver NCOA2 K780 acetylation, which stimulates its activation of PPARα in a SIRT6-dependent manner. These coordinated SIRT6 activities lead to regulation of whole-body respiratory exchange ratio and liver fat content, revealing the interactions whereby SIRT6 synchronizes various metabolic pathways, and suggest a mechanism by which SIRT6 maintains healthy liver

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

Potassium Level Variation Following Packed Cell Transfusion in Critically Ill Adult Patients—How Alert Should We Be?

One of the most clinically important effects following the administration of packed cell transfusion (PCT) is hyperkalemia, which can cause severe life-threatening cardiac arrhythmias. This retrospective population-based cohort study included adults hospitalized between January 2007 and December 2019 in a general intensive care unit for 24 h or more, with normal levels of serum potassium on admission. We assessed changes in serum potassium levels after administration of one unit of packed cells and sought to identify clinical parameters that may affect these changes. We applied adjusted linear mixed models to assess changes in serum potassium. The mean increase in serum potassium was 0.09 mEq/L (C.U 0.04–0.14, p-value < 0.001) among the 366 patients who were treated with a single PCT compared to those not treated with PCT. Increased serum potassium levels were also found in patients who required mechanical ventilation, and to a lesser degree in those treated with vasopressors. Hypertension, the occurrence of a cerebrovascular accident, and increased creatinine levels were all associated with reduced serum potassium levels. Due to the small rise in serum potassium levels following PCT, we do not suggest any particular follow-up measures for critically ill patients who receive PCT