RDH12 has been suggested to be one of the retinol dehydrogenases (RDH) involved in the vitamin A recycling system (visual cycle) in the eye. Loss of function mutations in the RDH12 gene were recently reported to be associated with autosomal recessive childhood-onset severe retinal dystrophy. Here we show that RDH12 localizes to the photoreceptor inner segments and that deletion of this gene in mice slows the kinetics of alltrans-retinal reduction, delaying dark adaptation. However, accelerated 11-cis-retinal production and increased susceptibility to light-induced photoreceptor apoptosis were also observed in Rdh12 ؊/؊ mice, suggesting that RDH12 plays a unique, nonredundant role in the photoreceptor inner segments to regulate the flow of retinoids in the eye. Thus, severe visual impairments of individuals with null mutations in RDH12 may likely be caused by light damage 1 .

To elucidate the possible role of 11-cis-retinol dehydrogenase in the visual cycle and/or 9-cis-retinoic acid biosynthesis, we generated mice carrying a targeted disruption of the 11-cis-retinol dehydrogenase gene. Homozygous 11-cis-retinol dehydrogenase mutants developed normally, including their retinas. There was no appreciable loss of photoreceptors. Recently, mutations in the 11-cis-retinol dehydrogenase gene in humans have been associated with fundus albipunctatus. In 11-cis-retinol dehydrogenase knockout mice, the appearance of the fundus was normal and punctata typical of this human hereditary ocular disease were not present. A second typical symptom associated with this disease is delayed dark adaptation. Homozygous 11-cis-retinol dehydrogenase mutants showed normal rod and cone responses. 11-cis-Retinol dehydrogenase knockout mice were capable of dark adaptation. At bleaching levels under which patients suffering from fundus albipunctatus could be detected unequivocally, 11-cis-retinol dehydrogenase knockout animals displayed normal dark adaptation kinetics. However, at high bleaching levels, delayed dark adaptation in 11-cis-retinol dehydrogenase knockout mice was noticed. Reduced 11-cis-retinol oxidation capacity resulted in 11-cis-retinol/13-cis-retinol and 11-cisretinyl/13-cis-retinyl ester accumulation. Compared with wild-type mice, a large increase in the 11-cis-retinyl ester concentration was noticed in 11-cis-retinol dehydrogenase knockout mice. In the murine retinal pigment epithelium, there has to be an additional mechanism for the biosynthesis of 11-cis-retinal which partially compensates for the loss of the 11-cis-retinol dehydrogenase activity. 11-cis-Retinyl ester formation is an important part of this adaptation process. Functional consequences of the loss of 11-cis-retinol dehydrogenase activity illustrate important differences in the compensation mechanisms between mice and humans. We furthermore demonstrate that upon 11-cis-retinol accumulation, the 13-cis-retinol concentration also increases. This retinoid is inapplicable to the visual processes, and we therefore speculate that it could be an important catabolic metabolite and its biosynthesis could be part of a process involved in regulating 11-cisretinol concentrations within the retinal pigment epithelium of 11-cis-retinol dehydrogenase knockout mice.Upon illumination of rhodopsin, the chromophore 11-cisretinal is isomerized to all-trans-retinal, which is subsequently released from the protein. Enzymes involved in the regeneration of 11-cis-retinal are part of the visual cycle (28). Two redox reactions are known to play a role in this cycle (48). One of these reactions is the reduction of all-trans-retinal to alltrans-retinol, catalyzed by retinol dehydrogenases present in the photoreceptor cells. A second reaction is the oxidation of 11-cis-retinol to 11-cis-retinal in the retinal pigment epithelium (RPE).Simon and coworkers and we previously reported the cloning of a retinol dehydrogenase highly expressed in the RPE (4, 37, 38)....

Using serial analysis of gene expression on cultured human keratinocytes we found high expression levels of genes putatively involved in host protection and defense, such as proteinase inhibitors and antimicrobial proteins. One of these expressed genes was the recently discovered cysteine proteinase inhibitor cystatin M/E that has not been characterized so far at the protein level with respect to tissue distribution and additional biologic properties. Here we report that cystatin M/E has a tissue-specific expression pattern in which high expression levels are restricted to the stratum granulosum of normal human skin, the stratum granulosum/spinosum of psoriatic skin, and the secretory coils of eccrine sweat glands. Low expression levels were found in the nasal cavity. The presence of cystatin M/E in skin and the lack of expression in a variety of other tissues was verified both at the protein level by immunohistochemistry or western blotting, and at the mRNA level by reverse transcriptase polymerase chain reaction or northern blotting. Using biotinylated hexapeptide probes we found that cystatin M/E is an efficient substrate for tissue type transglutaminase and for transglutaminases extracted from stratum corneum, and that it acts as an acyl acceptor but not as an acyl donor. Western blot analysis showed that recombinant cystatin M/E could be cross-linked to a variety of proteins extracted from stratum corneum. In vitro, we found that cystatin M/E expression in cultured keratinocytes is upregulated at the mRNA and protein level, upon induction of differentiation. We demonstrate that cystatin M/E, which has a putative signal peptide, is indeed a secreted protein and is found in vitro in culture supernatant and in vivo in human sweat by enzyme-linked immunosorbent assay or western blotting. Cystatin M/E showed moderate inhibition of cathepsin B but was not active against cathepsin C. We speculate that cystatin M/E is unlikely to be a physiologically relevant inhibitor of intracellular lysosomal cysteine proteinases but rather functions as an inhibitor of self and nonself cysteine proteinases that remain to be identified.

This document presents the Bonn PRINTEGER Consensus Statement: Working with Research Integrity—Guidance for research performing organisations. The aim of the statement is to complement existing instruments by focusing specifically on institutional responsibilities for strengthening integrity. It takes into account the daily challenges and organisational contexts of most researchers. The statement intends to make research integrity challenges recognisable from the work-floor perspective, providing concrete advice on organisational measures to strengthen integrity. The statement, which was concluded February 7th 2018, provides guidance on the following key issues: Providing information about research integrityProviding education, training and mentoringStrengthening a research integrity cultureFacilitating open dialogueWise incentive managementImplementing quality assurance proceduresImproving the work environment and work satisfactionIncreasing transparency of misconduct casesOpening up researchImplementing safe and effective whistle-blowing channelsProtecting the alleged perpetratorsEstablishing a research integrity committee and appointing an ombudspersonMaking explicit the applicable standards for research integrity

Meditation is a conscious mental process that induces a set of integrated physiologic changes termed the relaxation response. Functional magnetic resonance imaging (fMRI) was used to identify and characterize the brain regions that are active during a simple form of meditation. Significant (p<10(-7)) signal increases were observed in the group-averaged data in the dorsolateral prefrontal and parietal cortices, hippocampus/parahippocampus, temporal lobe, pregenual anterior cingulate cortex, striatum, and pre- and post-central gyri during meditation. Global fMRI signal decreases were also noted, although these were probably secondary to cardiorespiratory changes that often accompany meditation. The results indicate that the practice of meditation activates neural structures involved in attention and control of the autonomic nervous system.