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Schizophrenia is a severe chronic mental disorder with a high genetic component in its etiology. Several lines of study have suggested that synaptic dysfunction may underlie the pathogenesis of schizophrenia. Neuroligin proteins function as cell-adhesion molecules at post-synaptic membrane and play critical roles in synaptogenesis and synaptic maturation. In this study, we systemically sequenced all the exons and promoter region of neuroligin-2 (NLGN2) gene in a sample of 584 schizophrenia patients and 549 control subjects from Taiwan. In total, we identified 19 genetic variants, including six rare missense mutations such as R215H (one patient), V510M (two patients), R621H (one patient), A637T (two patients), P800L (one patient and one control) and A819S (one patient and one control). In silico analysis predicted that two patient-specific missense mutations, R215H and R621H, had damaging effect, whereas the other missense mutations were benign. Importantly, functional analysis with immunocytochemistry and electrophysiological recordings identified the R215H mutant as a loss-of-function mutant in inducing GABAergic synaptogenesis. Mechanistically, the synaptogenic deficiency of R215H mutant was due to its retention inside the endoplasmic reticulum and inability to be transported to cell membrane. Our study suggests that defects in GABAergic synapse formation in the brain may be an important contributing factor for the onset of schizophrenia. In the family study of this mutation, we found his elder brother also carried this mutation but did not have psychiatric symptoms, indicating that this mutation has incomplete penetrance, and thus the clinical relevance of this mutation should be interpreted with caution.

Background The two most commonly used modalities of teledermatology (TD) are store-and-forward (SF) and live-interactive (LI) TD. Existing studies have not compared these tools with respect to patient and provider satisfaction. Objective To systematically review all published studies of patient and provider satisfaction with SF and LI TD. Methods PubMed, EMBASE, and Cochrane databases were systematically searched for studies on provider or patient satisfaction with SF or LI TD between January 2000 and June 2016. Results Forty eligible studies were identified: 32 with SF TD, 10 with LI TD, and 2 evaluating both. With SF TD, 96% of studies assessing patient satisfaction and 82% of studies assessing provider satisfaction demonstrated satisfaction ( n = 24 and 17, respectively). With LI TD, 89% of studies assessing patient satisfaction and all studies assessing provider satisfaction revealed satisfaction (n = 9 and 6, respectively). Conclusion Patients and providers are satisfied with both SF and LI TD. Studies assessing satisfaction with LI have not been conducted in recent years, and have only been conducted in limited geographic patient populations. Further research assessing satisfaction with TD will help address any dissatisfaction with its uses and allow for increased support and funding of future programmes.

The anaerobic sulfatase maturating enzyme from Clostridium perfringens (anSMEcpe) catalyzes the two-electron oxidation of a cysteinyl residue on a cognate protein to a formyglycyl residue (FGly) using a mechanism that involves organic radicals. The FGly residue plays a unique role as a cofactor in a class of enzymes termed arylsulfatases, which catalyze the hydrolysis of various organosulfate monoesters. anSMEcpe has been shown to be a member of the radical S-adenosylmethionine (SAM) family of enzymes, [4Fe–4S] cluster–requiring proteins that use a 5’-deoxyadenosyl 5’-radical (5’-dA•) generated from a reductive cleavage of SAM to initiate radical-based catalysis. Herein, we show that anSMEcpe contains in addition to the [4Fe–4S] cluster harbored by all radical SAM (RS) enzymes, two additional [4Fe–4S] clusters, similar to the radical SAM protein AtsB, which catalyzes the two-electron oxidation of a seryl residue to a FGly residue. We show by size-exclusion chromatography that both AtsB and anSMEcpe are monomeric proteins, and site-directed mutagenesis studies on AtsB reveal that individual Cys→Ala substitutions at seven conserved positions result in insoluble protein, consistent with those residues acting as ligands to the two additional [4Fe–4S] clusters. Ala substitutions at an additional conserved Cys residue (C291 in AtsB; C276 in anSMEcpe) afford proteins that display intermediate behavior. These proteins exhibit reduced solubility and drastically reduced activity, behavior that is conspicuously similar to that of a critical Cys residue in BtrN, another radical SAM dehydrogenase [Grove, T. L., et al (2010) Biochemistry, 49, 3783–3785]. We also show that wild-type anSMEcpe acts on peptides containing other oxidizeable amino acids at the target position. Moreover, we show that the enzyme will convert threonyl peptides to the corresponding ketone product, and also allo-threonyl peptides, but with a significantly reduced efficiency, suggesting that the proS hydrogen atom of the normal cysteinyl substrate is stereoselectively removed during turnover. Lastly, we show that the electron generated during catalysis by AtsB and anSMEcpe can utilized for multiple turnovers, albeit through a reduced flavodoxin-mediated pathway.

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