Bacterial members of the neurotransmitter:sodium symporter (NSS) family perform Na+-dependent amino-acid uptake and extrude H+ in return. Previous NSS structures represent intermediates of Na+/substrate binding or intracellular release, but not the inward-to-outward return transition. Here we report crystal structures of Aquifex aeolicus LeuT in an outward-oriented, Na+- and substrate-free state likely to be H+-occluded. We find a remarkable rotation of the conserved Leu25 into the empty substrate-binding pocket and rearrangements of the empty Na+ sites. Mutational studies of the equivalent Leu99 in the human serotonin transporter show a critical role of this residue on the transport rate. Molecular dynamics simulations show that extracellular Na+ is blocked unless Leu25 is rotated out of the substrate-binding pocket. We propose that Leu25 facilitates the inward-to-outward transition by compensating a Na+- and substrate-free state and acts as the gatekeeper for Na+ binding that prevents leak in inward-outward return transitions.
The prognosis associated with clear cell renal carcinoma (ccRCC) can vary widely and novel molecular prognostic markers are needed to assess prognosis at an earlier stage. Several gene products have been investigated for this purpose, but none of them have been implemented in clinical practice. Here we hypothesized that we, using TaqMan® Array, could identify superior prognostic messenger RNA (mRNA)s in long-term follow-up. Messenger RNA level of 19 candidate genes was investigated in 97 patients with ccRCC. Three genes impacted significantly on prognosis in both univariate and multivariate analysis. In univariate analysis, CSNK2A1 was a strong indicator of a poor overall survival (OS) (HR = 5.01, p< 0.001), disease specific survival (DSS) (HR = 6.21, p = 0.007) and progression free survival (PFS) (HR = 5.93, p = 0.005). High expression of SPP1 was associated to poor PFS (HR = 4.41, p = 0.04). DEFB1 was associated with a better PFS (HR = 0.24, p = 0.006). In multivariate analysis, CSNK2A1 was associated to a worse OS (HR = 3.56, p = 0.008) and PFS (HR = 3.84, p = 0.005), whereas SPP1 was an independent predictor of a worse PFS (HR = 3.46, p = 0.007) and DEFB1 of a better PFS (HR = 0.37, p = 0.027). These results show that with TaqMan®) Array we could identify three superior gene products related to prognosis. Further studies are needed to elucidate the pathways and roles of these genes in renal cacer development.
Background:The serotonin transporter (SERT) mediates neuronal reuptake of serotonin and is inhibited by most antidepressants. Results: A dualistic conformational response in SERT reveals a high affinity state in response to serotonin. Conclusion: Membrane cholesterol modulates the dualistic conformational response to serotonin in SERT. Significance: The interplay between the conformational responses in SERT and cholesterol is important for understanding an important pharmaceutical target in depression.
A combination of 4 genes, HMBS, PPIA, ATP5J, and TBP, is a possible reference in renal tumor gene expression analysis by reverse transcription polymerase chain reaction. A combination of four genes, HMBS, PPIA, ATP5J and TBP, being stably expressed in tissues from RCC is possible reference genes for gene expression analysis.
Objectives: Adverse drug reactions (ADRs) are one among the leading causes of morbidity and mortality worldwide. Anesthetics might inflict a significant number of potential ADRs which require consistent monitoring. The aim of the study was to
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