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Importance: GPN-loop GTPases have been found to be crucial for eukaryotic RNA polymerase II assembly and nuclear trafficking. Despite their ubiquitous occurrence in eukaryotes and archaea, the mechanism by which these GTPases mediate their function is unknown. Our study on an archaeal representative from Sulfolobus acidocaldarius showed that these dimeric GTPases undergo large-scale conformational changes upon GTP hydrolysis, which can be summarized as a lock-switch-rock mechanism. The observed requirement of Sa GPN for motility appears to be due to its large footprint on the archaeal proteome., Competing Interests: The authors declare no conflict of interest.

Photolyases, a ubiquitous class of flavoproteins, use blue light to repair DNA photolesions. In this work, we determined the structural mechanism of the photolyase-catalyzed repair of a cyclobutane pyrimidine dimer (CPD) lesion using time-resolved serial femtosecond crystallography (TR-SFX). We obtained 18 snapshots that show time-dependent changes in four reaction loci. We used these results to create a movie that depicts the repair of CPD lesions in the picosecond-to-nanosecond range, followed by the recovery of the enzymatic moieties involved in catalysis, completing the formation of the fully reduced enzyme-product complex at 500 nanoseconds. Finally, back-flip intermediates of the thymine bases to reanneal the DNA were captured at 25 to 200 microseconds. Our data cover the complete molecular mechanism of a photolyase and, importantly, its chemistry and enzymatic catalysis at work across a wide timescale and at atomic resolution.

Objective: The aim of the study is to examine the incidence and risk factors for death among neonates who developed neonatal seizures (NS) in an ethnically distinctive community with high consanguinity rate in Israel., Methods: Retrospective study was conducted at a single institution on data between January 2001 and January 2016. All neonates diagnosed with NS developed up to age 28 days were included. Mortality was defined as death within the first year of life., Results: Of all 69,460 neonates born during the study period, 118 (1.7 per 1,000 live births) developed NS; 35 (29.7%) died within the first year while 83 (70.3%) survived. The leading causes of death were developmental brain malformation (31.4%), genetic/metabolic (20%), hypoxic ischemic encephalopathy (20%), intracranial hemorrhage (11.4%) and infections (11.4%). Any consanguinity between the parents was found in 18 and 14.6% among the survivors and deceased groups, respectively ( p  = 0.24). Developmental brain malformations that lead to death were present in 3.6 and 31.4% in the survivors and deceased groups, respectively ( p  = 0.001; relative risk 8.70; 95% confidence interval 2.58-29.27). Stepwise backward logistic regression analysis revealed that developmental brain malformations ( p  < 0.0001), use of more than one antiepileptic medication ( p  = 0.006), and multiorgan failure ( p  = 0.004) were significant risk factors that predicted death., Conclusion: The results of the current study show that developmental brain malformations that cause NS were the leading risk factor for death., Competing Interests: All authors have indicated they have no potential conflicts of interest to disclose., (Thieme. All rights reserved.)

Epistaxis is a common debilitating manifestation in hereditary hemorrhagic telangiectasia (HHT), due to mucocutaneous telangiectases. The epistaxis can be difficult to control despite available treatments. Dysregulated angiogenesis has been shown to be associated with telangiectases formation. Topical propranolol has demonstrated antiangiogenic properties. We performed a two-phase study, i.e., a double-blind placebo-controlled phase, followed by an open-label phase. The aim of the study was assessment of safety and efficacy of nasal propranolol gel in HHT-related epistaxis. Twenty participants with moderate-severe HHT-related epistaxis were randomized to eight weeks of propranolol gel 1.5%, or placebo 0.5 cc, applied to each nostril twice daily; and continued propranolol for eight weeks in an open-label study. For the propranolol group, the epistaxis severity score (ESS) improved significantly (-2.03 ± 1.7 as compared with -0.35 ± 0.68 for the placebo group, p = 0.009); hemoglobin levels improved significantly (10.5 ± 2.6 to 11.4 ± 2.02 g/dL, p = 0.009); and intravenous iron and blood transfusion requirement decreased. The change in nasal endoscopy findings was not significant. During the open-label period, the ESS score improved significantly in the former placebo group (-1.99 ± 1.41, p = 0.005). The most common adverse event was nasal mucosa burning sensation. No cardiovascular events were reported. Our results suggest that topical propranolol gel is safe and effective in HHT-related epistaxis.

The metV genomic island in the chromosome of uropathogenic Escherichia coli (UPEC) encodes a putative transcription factor and a sugar permease of the phosphotransferase system (PTS), which are predicted to compose a Bgl-like sensory system. The presence of these two genes, hereby termed pafR and pafP, respectively, has been previously shown to correlate with isolates causing clinical syndromes. We show here that deletion of both genes impairs the ability of the resulting mutant to infect the CBA/J mouse model of ascending urinary tract infection compared to that of the parent strain, CFT073. Expressing the two genes in trans in the two-gene knockout mutant complemented full virulence. Deletion of either gene individually generated the same phenotype as the double knockout, indicating that both pafR and pafP are important to pathogenesis. We screened numerous environmental conditions but failed to detect expression from the promoter that precedes the paf genes in vitro, suggesting that they are in vivo induced (ivi). Although PafR is shown here to be capable of functioning as a transcriptional antiterminator, its targets in the UPEC genome are not known. Using microarray analysis, we have shown that expression of PafR from a heterologous promoter in CFT073 affects expression of genes related to bacterial virulence, biofilm formation, and metabolism. Expression of PafR also inhibits biofilm formation and motility. Taken together, our results suggest that the paf genes are implicated in pathogenesis and that PafR controls virulence genes, in particular biofilm formation genes., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)