The Potorous CPD Photolyase Rescues a Cryptochrome-Deficient Mammalian Circadian Clock

Despite the sequence and structural conservation between cryptochromes and photolyases, members of the cryptochrome/photolyase (flavo)protein family, their functions are divergent. Whereas photolyases are DNA repair enzymes that use visible light to lesion-specifically remove UV-induced DNA damage, cryptochromes act as photoreceptors and circadian clock proteins. To address the functional diversity of cryptochromes and photolyases, we investigated the effect of ectopically expressed Arabidopsis thaliana (6-4)PP photolyase and Potorous tridactylus CPD-photolyase (close and distant relatives of mammalian cryptochromes, respectively), on the performance of the mammalian cryptochromes in the mammalian circadian clock. Using photolyase transgenic mice, we show that Potorous CPD-photolyase affects the clock by shortening the period of behavioral rhythms. Furthermore, constitutively expressed CPD-photolyase is shown to reduce the amplitude of circadian oscillations in cultured cells and to inhibit CLOCK/BMAL1 driven transcription by interacting with CLOCK. Importantly, we show that Potorous CPD-photolyase can restore the molecular oscillator in the liver of (clock-deficient) Cry1/Cry2 double knockout mice. These data demonstrate that a photolyase can act as a true cryptochrome. These findings shed new light on the importance of the core structure of mammalian cryptochromes in relation to its function in the circadian clock and contribute to our further understanding of the evolution of the cryptochrome/photolyase protein family

The validation of a new measure quantifying the social quality of life of ethnically diverse older women: two cross-sectional studies

<p>Abstract</p> <p>Background</p> <p>To our knowledge, the available psychometric literature does not include an instrument for the quantification of social quality of life among older women from diverse ethnic backgrounds. To address the need for a tool of this kind, we conducted two studies to assess the initial reliability and validity of a new instrument. The latter was created specifically to quantify the contribution of a) social networks and resources (e.g., family, friends, and community) as well as b) one's perceived power and respect within family and community to subjective well-being in non-clinical, ethnically diverse populations of older women.</p> <p>Methods</p> <p>In Study 1, we recruited a cross-sectional sample of primarily non-European-American older women (<it>N </it>= 220) at a variety of community locations. Participants were administered the following: a short screener for dementia; a demographic list; an initial pool of 50 items from which the final items of the new Older Women's Social Quality of Life Inventory (OWSQLI) were to be chosen (based on a statistical criterion to apply to the factor analysis findings); the Single Item Measure of Social Support (SIMSS); and the Medical Outcome Study 36-item Short-Form Health Survey (MOS SF-36). Study 2 was conducted on a second independent sample of ethnically diverse older women. The same recruitment strategies, procedures, and instruments as those of Study 1 were utilized in Study 2, whose sample was comprised of 241 older women with mostly non-European-American ethnic status.</p> <p>Results</p> <p>In Study 1, exploratory factor analysis of the OWSQLI obtained robust findings: the total variance explained by one single factor with the final selection of 22 items was over 44%. The OWSQLI demonstrated strong internal consistency (<it>α </it>= .92, <it>p </it>< .001), adequate criterion validity with the SIMSS (<it>r </it>= .33; <it>p </it>< .01), and (as expected) moderate concurrent validity with the MOS SF-36 for both physical (<it>r </it>= .21; <it>p </it>< .01) and mental (<it>r </it>= .26; <it>p </it>< .01) quality of life. In order to confirm the validity of the 22-item OWSQLI scale that emerged from Study 1 analyses, we replicated those analyses in Study 2, although using confirmatory factor analysis. The total variance accounted for by one factor was about 42%, again quite high and indicative of a strong single-factor solution. Study 2 data analyses yielded the same strong reliability findings (i.e., <it>α </it>= .92, <it>p </it>< .001). The 22-item OWSQLI was correlated with the SIMSS (<it>r </it>= .27, <it>p </it>< .001) in the expected direction. Finally, correlations with the MOS SF- 36 demonstrated moderate concurrent validity for physical (<it>r </it>= .14; <it>p </it>< .01) and mental (<it>r </it>= .18; <it>p </it>< .01) quality of life, as expected.</p> <p>Conclusions</p> <p>The findings of these two studies highlight the potential for our new tool to provide a valid measure of older women's social quality of life, yet they require duplication in longitudinal research. Interested clinicians should consider using the OWSQLI in their assessment battery to identify older women's areas of lower versus higher social quality of life, and should establish the maximization of patients' social quality of life as an important therapeutic goal, as this variable is significantly related to both physical and mental health.</p

Time spent in sedentary posture is associated with waist circumference and cardiovascular risk

Background The relationship between metabolic risk and time spent sitting, standing and stepping has not been well established. The present study aimed to determine associations of objectively measured time spent siting, standing and stepping, with coronary heart disease (CHD) risk. Methods A cross-sectional study of healthy non-smoking Glasgow postal workers, n=111 (55 office-workers, 5 women, and 56 walking/delivery-workers, 10 women), who wore activPAL physical activity monitors for seven days. Cardiovascular risks were assessed by metabolic syndrome categorisation and 10-y PROCAM risk. Results Mean(SD) age was 40(8) years, BMI 26.9(3.9)kg/m-2 and waist circumference 95.4(11.9)cm. Mean(SD) HDL-cholesterol 1.33(0.31), LDL-cholesterol 3.11(0.87), triglycerides 1.23(0.64)mmol/l and 10-y PROCAM risk 1.8(1.7)%. Participants spent mean(SD) 9.1(1.8)h/d sedentary, 7.6(1.2)h/d sleeping, 3.9(1.1)h/d standing and 3.3(0.9)h/d stepping, accumulating 14,708(4,984)steps/d in 61(25) sit-to-stand transitions per day. In univariate regressions - adjusting for age, sex, family history of CHD, shift worked, job type and socio-economic status - waist circumference (p=0.005), fasting triglycerides (p=0.002), HDL-cholesterol (p=0.001) and PROCAM-risk (p=0.047) were detrimentally associated with sedentary time. These associations remained significant after further adjustment for sleep, standing and stepping in stepwise regression models. However, after further adjustment for waist circumference, the associations were not significant. Compared to those without the metabolic syndrome, participants with the metabolic syndrome were significantly less active – fewer steps, shorter stepping duration and longer time sitting. Those with no metabolic syndrome features walked &gt;15,000 steps/day, or spent &gt;7h/day upright. Conclusion Longer time spent in sedentary posture is significantly associated with higher CHD risk and larger waist circumference

Sexually Dimorphic Serotonergic Dysfunction in a Mouse Model of Huntington's Disease and Depression

Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT) and the forced-swimming test (FST). The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT1A receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT2A receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2) mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice

Transcriptional Activity and Nuclear Localization of Cabut, the Drosophila Ortholog of Vertebrate TGF-β-Inducible Early-Response Gene (TIEG) Proteins

BackgroundCabut (Cbt) is a C2H2-class zinc finger transcription factor involved in embryonic dorsal closure, epithelial regeneration and other developmental processes in Drosophila melanogaster. Cbt orthologs have been identified in other Drosophila species and insects as well as in vertebrates. Indeed, Cbt is the Drosophila ortholog of the group of vertebrate proteins encoded by the TGF-ß-inducible early-response genes (TIEGs), which belong to Sp1-like/Krüppel-like family of transcription factors. Several functional domains involved in transcriptional control and subcellular localization have been identified in the vertebrate TIEGs. However, little is known of whether these domains and functions are also conserved in the Cbt protein.Methodology/Principal FindingsTo determine the transcriptional regulatory activity of the Drosophila Cbt protein, we performed Gal4-based luciferase assays in S2 cells and showed that Cbt is a transcriptional repressor and able to regulate its own expression. Truncated forms of Cbt were then generated to identify its functional domains. This analysis revealed a sequence similar to the mSin3A-interacting repressor domain found in vertebrate TIEGs, although located in a different part of the Cbt protein. Using β-Galactosidase and eGFP fusion proteins, we also showed that Cbt contains the bipartite nuclear localization signal (NLS) previously identified in TIEG proteins, although it is non-functional in insect cells. Instead, a monopartite NLS, located at the amino terminus of the protein and conserved across insects, is functional in Drosophila S2 and Spodoptera exigua Sec301 cells. Last but not least, genetic interaction and immunohistochemical assays suggested that Cbt nuclear import is mediated by Importin-α2.Conclusions/SignificanceOur results constitute the first characterization of the molecular mechanisms of Cbt-mediated transcriptional control as well as of Cbt nuclear import, and demonstrate the existence of similarities and differences in both aspects of Cbt function between the insect and the vertebrate TIEG proteins

Reading tea leaves worldwide: Decoupled drivers of initial litter decomposition mass‐loss rate and stabilization

The breakdown of plant material fuels soil functioning and biodiversity. Currently, process understanding of global decomposition patterns and the drivers of such patterns are hampered by the lack of coherent large-scale datasets. We buried 36,000 individual litterbags (tea bags) worldwide and found an overall negative correlation between initial mass-loss rates and stabilization factors of plant-derived carbon, using the Tea Bag Index (TBI). The stabilization factor quantifies the degree to which easy-to- degrade components accumulate during early-stage decomposition (e.g. by environmental limitations). However, agriculture and an interaction between moisture and temperature led to a decoupling between initial mass-loss rates and stabilization, notably in colder locations. Using TBI improved mass-loss estimates of natural litter compared to models that ignored stabilization. Ignoring the transformation of dead plant material to more recalcitrant substances during early-stage decomposition, and the environmental control of this transformation, could overestimate carbon losses during early decomposition in carbon cycle models

Male, National, and Religious Collective Narcissism Predict Sexism

Results of three cross-sectional studies indicate that sexism in Poland is associated with collective narcissism—a belief that one’s own group’s (the in-group’s) exaggerated exceptionality is not sufficiently recognized by others—with reference to three social identities: male, religious, and national. In Study 1 (n = 329), male collective narcissism was associated with sexism. This relationship was sequentially mediated by precarious manhood and traditional gender beliefs. In Study 2 (n = 877), Catholic collective narcissism predicted tolerance of violence against women (among men and women) over and above religious fundamentalism and in contrast to intrinsic religiosity. In Study 3 (n = 1070), national collective narcissism was associated with hostile sexism among men and women and with benevolent sexism more strongly among women than among men. In contrast, national in-group satisfaction—a belief that the nation is of a high value—predicted rejection of benevolent and hostile sexism among women but was positively associated with hostile and benevolent sexism among men. Among men and women collective narcissism was associated with tolerance of domestic violence against women, whereas national in-group satisfaction was associated with rejection of violence against women

Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications

The serotonergic system of the brain is complex, with an extensive innervation pattern covering all brain regions and endowed with at least 15 different receptors (each with their particular distribution patterns), specific reuptake mechanisms and synthetic processes. Many aspects of the functioning of the serotonergic system are still unclear, partially because of the difficulty of measuring physiological processes in the living brain. In this review we give an overview of the conventional methods of measuring serotonin synthesis and methods using positron emission tomography (PET) tracers, more specifically with respect to serotonergic function in affective disorders. Conventional methods are invasive and do not directly measure synthesis rates. Although they may give insight into turnover rates, a more direct measurement may be preferred. PET is a noninvasive technique which can trace metabolic processes, like serotonin synthesis. Tracers developed for this purpose are α-[11C]methyltryptophan ([11C]AMT) and 5-hydroxy-L-[β-11C]tryptophan ([11C]5-HTP). Both tracers have advantages and disadvantages. [11C]AMT can enter the kynurenine pathway under inflammatory conditions (and thus provide a false signal), but this tracer has been used in many studies leading to novel insights regarding antidepressant action. [11C]5-HTP is difficult to produce, but trapping of this compound may better represent serotonin synthesis. AMT and 5-HTP kinetics are differently affected by tryptophan depletion and changes of mood. This may indicate that both tracers are associated with different enzymatic processes. In conclusion, PET with radiolabelled substrates for the serotonergic pathway is the only direct way to detect changes of serotonin synthesis in the living brain