The human circadian metabolome

The circadian clock orchestrates many aspects of human physiology, and disruption of this clock has been implicated in various pathologies, ranging from cancer to metabolic syndrome and diabetes. Although there is evidence that metabolism and the circadian clockwork are intimately linked on a transcriptional level, whether these effects are directly under clock control or are mediated by the rest-activity cycle and the timing of food intake is unclear. To answer this question, we conducted an unbiased screen in human subjects of the metabolome of blood plasma and saliva at different times of day. To minimize indirect effects, subjects were kept in a 40-h constant routine of enforced posture, constant dim light, hourly isocaloric meals, and sleep deprivation. Under these conditions, we found that ~15% of all identified metabolites in plasma and saliva were under circadian control, most notably fatty acids in plasma and amino acids in saliva. Our data suggest that there is a strong direct effect of the endogenous circadian clock on multiple human metabolic pathways that is independent of sleep or feeding. In addition, they identify multiple potential small-molecule biomarkers of human circadian phase and sleep pressure.

God, the WTO – and hunger

Considering that endemic hunger is a consequence of poverty, and that food is arguably the most basic of all human needs, this book chapter shows one of the more prominent examples of rules and policy fragmentation but also one of the most blatant global governance problems. The three monotheistic religions Judaism, Christians and Islam are surprisingly unanimous about God’s prescriptions on hunger or, put theologically, on what can be said, or should be said, about the interpretations and traditions which, taken together, form the respective and differentiated traditions, identities and views of these beliefs on how to deal with poverty and hunger. A clear social ethos, in the form of global needs satisfaction, runs through both Jewish and Christian texts, and the Qur’an (Zakat). It confirms the value inversion between the world of the mighty and that of the hungry. The message is clear: because salvation is available only through the grace of God, those who have must give to those who have not. This is not charity: it is an inversion of values which can not be addressed by spending 0.7% of your GDP on ODA, and the implication of this sense of redistributive justice is that social offenders will be subject to the Last Judgement. Interestingly, these religious scriptures found their way directly into the human rights treaties adopted by the United Nations and ratified by the parliaments, as a legal base for the duty to protect, to respect and to remedy. On the other side the contradiction with international trade law is all the more flagrant, and it has a direct bearing on poverty: systematic surplus food dumping is still allowed under WTO rules, despite the declared objective ‘to establish a fair and market-oriented agricultural trading system’. A way forward would be a kind of ‘bottom up’ approach by focusing on extreme cases of food insecurity caused by food dumping, or by export restrictions where a direct effect of food insecurity in other countries can be established. Also, international financing institutions need to review their policies and lending priorities. The same goes for the bilateral investment treaties and a possible ‘public interest’ clause, at least in respect of agricultural land acquisitions in vulnerable countries. The bottom line is this: WTO rules cannot entail a right to violate other, equally binding treaty obligations when its membership as a whole claims to contribute to the Millennium Development Goals and pledges to eradicate extreme poverty and hunger.

Hope as a resource for self-directed career management: Investigatiing mediating effects on proactive career behaviors, life and job satisfaction

ABSTRACT Hope is increasingly recognized as an important psychological resource for career development, yet the empirical research on its functioning in this domain is sparse. This paper describes an investigation of how dispositional hope is related to career decidedness, career planning, and career self-efficacy beliefs and whether these more proximal career attitudes mediate the effects of hope on proactive career behaviors, life satisfaction, and job satisfaction. This investigation was conducted using two independent samples of university students (N = 1,334) and working professionals (N = 233). The results showed that in both samples, hope was significantly related but empirically distinct from career variables. In both samples, hope had a direct effect on proactive career behaviors, partially mediated by more career planning. Hope had significant direct and indirect effects on life satisfaction among students, mediated by the three career development attitudes. Although hope was significantly correlated with job satisfaction among employees, no direct effect of hope was found in the mediation model, but an indirect effect through career decidedness was found. The results suggest that hope is an important resource for proactive career development at different career stages and that the positive relation of hope to life and job satisfaction can partially be attributed to the positive relation between hope and favorable career development attitudes.

Perceived organizational support and intention to stay in host countries among self-initiated expatriates: the role of career satisfaction and networks

Previous literature in SIE (self-initiated expatriation) has been mostly focused on an individual perspective. Studies on SIEs in organizational context are scarce. The current paper sought to examine the effect of perceived organizational support (POS) on SIE employees’ intention to stay in the host country, mediated by career satisfaction. Furthermore, we examined the moderating roles of career-related social networks with host and home country nationals on the effectiveness of POS. Data from 112 SIE employees in Germany were collected and analyzed. Empirical results partially supported our proposed model: there were significant negative indirect effect between POS and intention to stay, when career network size with home country nationals was high. The direct effect between POS and intention to stay was positive. For HR practice, our paper gave insight to understand SIE employees’ needs for support and mobility preferences, which can help organizations to develop more targeted HR development measures and assignment strategies for them.

Radiotherapy for renal-cell carcinoma

Renal-cell carcinoma is considered to be a radioresistant tumour, but this notion might be wrong. If given in a few (even single) fractions, but at a high fraction dose, stereotactic body radiotherapy becomes increasingly important in the management of renal-cell carcinoma, both in primary settings and in treatment of oligometastatic disease. There is an established biological rationale for the radiosensitivity of renal-cell carcinoma to stereotactic body radiotherapy based on the ceramide pathway, which is activated only when a high dose per fraction is given. Apart from the direct effect of stereotactic body radiotherapy on renal-cell carcinoma, stereotactic body radiotherapy can also induce an abscopal effect. This effect, caused by immunological processes, might be enhanced when targeted drugs and stereotactic body radiotherapy are combined. Therefore, rigorous, prospective randomised trials involving a multidisciplinary scientific panel are needed urgently.

Effects of depressive symptoms on antecedents of lapses during a smoking cessation attempt: an ecological momentary assessment study

AIMS: To investigate pathways through which momentary negative affect and depressive symptoms affect risk of lapse during smoking cessation attempts. DESIGN: Ecological momentary assessment was carried out during 2 weeks after an unassisted smoking cessation attempt. A 3-month follow-up measured smoking frequency. SETTING: Data were collected via mobile devices in German-speaking Switzerland. PARTICIPANTS: A total of 242 individuals (age 20-40, 67% men) reported 7112 observations. MEASUREMENTS: Online surveys assessed baseline depressive symptoms and nicotine dependence. Real-time data on negative affect, physical withdrawal symptoms, urge to smoke, abstinence-related self-efficacy and lapses. FINDINGS: A two-level structural equation model suggested that on the situational level, negative affect increased the urge to smoke and decreased self-efficacy (β = 0.20; β = -0.12, respectively), but had no direct effect on lapse risk. A higher urge to smoke (β = 0.09) and lower self-efficacy (β = -0.11) were confirmed as situational antecedents of lapses. Depressive symptoms at baseline were a strong predictor of a person's average negative affect (β = 0.35, all P < 0.001). However, the baseline characteristics influenced smoking frequency 3 months later only indirectly, through influences of average states on the number of lapses during the quit attempt. CONCLUSIONS: Controlling for nicotine dependence, higher depressive symptoms at baseline were associated strongly with a worse longer-term outcome. Negative affect experienced during the quit attempt was the only pathway through which the baseline depressive symptoms were associated with a reduced self-efficacy and increased urges to smoke, all leading to the increased probability of lapses.

The heparan sulfate proteoglycan agrin contributes to barrier properties of mouse brain endothelial cells by stabilizing adherens junctions

Barrier characteristics of brain endothelial cells forming the blood-brain barrier (BBB) are tightly regulated by cellular and acellular components of the neurovascular unit. During embryogenesis, the accumulation of the heparan sulfate proteoglycan agrin in the basement membranes ensheathing brain vessels correlates with BBB maturation. In contrast, loss of agrin deposition in the vasculature of brain tumors is accompanied by the loss of endothelial junctional proteins. We therefore wondered whether agrin had a direct effect on the barrier characteristics of brain endothelial cells. Agrin increased junctional localization of vascular endothelial (VE)-cadherin, β-catenin, and zonula occludens-1 (ZO-1) but not of claudin-5 and occludin in the brain endothelioma cell line bEnd5 without affecting the expression levels of these proteins. This was accompanied by an agrin-induced reduction of the paracellular permeability of bEnd5 monolayers. In vivo, the lack of agrin also led to reduced junctional localization of VE-cadherin in brain microvascular endothelial cells. Taken together, our data support the notion that agrin contributes to barrier characteristics of brain endothelium by stabilizing the adherens junction proteins VE-cadherin and β-catenin and the junctional protein ZO-1 to brain endothelial junctions.

A Gendered Triangle? Intergenerational Social Mobility in 20th Century Switzerland

In the light of the dramatically changed social structure of women, surprisingly little gender differences have been found in temporal changes of effects of social origin on occupational class. Using a recently developed methodological approach and Swiss data on birth cohorts from 1925 to 1978, this paper takes a closer look by considering not only the total effect of social origin but also the individual elements of the indirect effect mediated by individual’s education. It finds that this indirect path have changed indeed differently for women and men, but the findings on the direct effect remain mixed, partially because this path seems to be especially sensitive to the conceptualization of social class.

Larger visual stimuli are perceived to last longer from time to time: The internal clock is not affected by nontemporal visual stimulus size

Performance on interval timing is often explained by the assumption of an internal clock based on neural counting. According to this account, a neural pacemaker generates pulses, and the number of pulses relating to a physical time interval is recorded by a counter. Thus, the number of accumulated pulses is the internal representation of this interval. Several studies demonstrated that large visual stimuli are perceived to last longer than smaller ones presented for the same duration. The present study was designed to investigate whether nontemporal visual stimulus size directly affects the internal clock. For this purpose, a temporal reproduction task was applied. Sixty participants were randomly assigned to one of two experimental conditions with stimulus size being experimentally varied within either the target or the reproduction interval. A direct effect of nontemporal stimulus size on the pacemaker-counter system should become evident irrespective of whether stimulus size was experimentally varied within the target or the reproduction interval. An effect of nontemporal stimulus size on reproduced duration only occurred when stimulus size was varied during the target interval. This finding clearly argues against the notion that nontemporal visual stimulus size directly affects the internal clock. Furthermore, our findings ruled out a decisional bias as a possible cause of the observed differential effect of stimulus size on reproduced duration. Rather the effect of stimulus size appeared to originate from the memory stage of temporal information processing at which the timing signal from the pacemaker-counter component is encoded in reference memory.

Using the theory of planned behaviour to model antecedents of surgical checklist use: a cross-sectional study.

BACKGROUND Compliance with surgical checklist use remains an obstacle in the context of checklist implementation programs. The theory of planned behaviour was applied to analyse attitudes, perceived behaviour control, and norms as psychological antecedents of individuals' intentions to use the checklist. METHODS A cross-sectional survey study with staff (N = 866) of 10 Swiss hospitals was conducted in German and French. Group mean differences between individuals with and without managerial function were computed. Structural equation modelling and confirmatory factor analysis was applied to investigate the structural relation between attitudes, perceived behaviour control, norms, and intentions. RESULTS Significant mean differences in favour of individuals with managerial function emerged for norms, perceived behavioural control, and intentions, but not for attitudes. Attitudes and perceived behavioural control had a significant direct effect on intentions whereas norms had not. CONCLUSIONS Individuals with managerial function exhibit stronger perceived behavioural control, stronger norms, and stronger intentions. This could be applied in facilitating checklist implementation. The structural model of the theory of planned behaviour remains stable across groups, indicating a valid model to describe antecedents of intentions in the context of surgical checklist implementation.

Active intravenous drug use during chronic hepatitis C therapy does not reduce sustained virological response rates in adherent patients

Reluctance has been expressed about treating chronic hepatitis C in active intravenous (IV) drug users (IDUs), and this is found in both international guidelines and routine clinical practice. However, the medical literature provides no evidence for an unequivocal treatment deferral of this risk group. We retrospectively analyzed the direct effect of IV drug use on treatment outcome in 500 chronic hepatitis C patients enrolled in the Swiss Hepatitis C Cohort Study. Patients were eligible for the study if they had their serum hepatitis C virus (HCV) RNA tested 6 months after the end of treatment and at least one visit during the antiviral therapy, documenting the drug use status. Five hundred patients fulfilled the inclusion criteria (199 were IDU and 301 controls). A minimum exposure to 80% of the scheduled cumulative dose of antivirals was reached in 66.0% of IDU and 60.5% of controls (P = NS). The overall sustained virological response (SVR) rate was 63.6%. Active IDU reached a SVR of 69.3%, statistically not significantly different from controls (59.8%). A multivariate analysis for treatment success showed no significant negative influence of active IV drug use. In conclusion, our study shows no relevant direct influence of IV drugs on the efficacy of anti-HCV therapy among adherent patients.

Streptococcus pneumoniae capsule determines disease severity in experimental pneumococcal meningitis.

Streptococcus pneumoniaebacteria can be characterized into over 90 serotypes according to the composition of their polysaccharide capsules. Some serotypes are common in nasopharyngeal carriage whereas others are associated with invasive disease, but when carriage serotypes do invade disease is often particularly severe. It is unknown whether disease severity is due directly to the capsule type or to other virulence factors. Here, we used a clinical pneumococcal isolate and its capsule-switch mutants to determine the effect of capsule, in isolation from the genetic background, on severity of meningitis in an infant rat model. We found that possession of a capsule was essential for causing meningitis. Serotype 6B caused significantly more mortality than 7F and this correlated with increased capsule thickness in the cerebrospinal fluid (CSF), a stronger inflammatory cytokine response in the CSF and ultimately more cortical brain damage. We conclude that capsule type has a direct effect on meningitis severity. This is an important consideration in the current era of vaccination targeting a subset of capsule types that causes serotype replacement.

Antibodies against major histocompatibility complex class II antigens directly inhibit the growth of T cells infected with Theileria parva without affecting their state of activation

We have analyzed the effect of antibodies (Abs) directed against major histocompatibility complex (MHC) class II Abs on the proliferation of Theileria parva-infected (Tpi) T cells. Anti-MHC class II Abs exert a direct effect on Tpi T cells causing an acute block in their proliferation. The inhibition does not involve apoptosis and is also entirely reversible. The rapid arrest of DNA synthesis caused by anti-MHC class II Abs is not due to interference with the state of activation of the T cells since the transcriptional activator NF-kappa B remains activated in arrested cells. In addition, interleukin 2 (IL-2), IL-2R, and c-myc gene expression are also unaffected. By analyzing the cell-cycle phase distribution of inhibited cells, it could be shown that cells in all phases of the cell cycle are inhibited. The signal transduction pathway that results in inhibition was shown to be independent of protein kinase C and extracellular Ca2+. Tyrosine kinase inhibitors, however, partly reduced the level of inhibition and, conversely, phosphatase inhibitors enhanced it. The possible relevance of this phenomenon in other systems is discussed.

INHIBITION OF THE MITOCHONDRIAL RESPIRATION OF TUMOR CELLS BY SOLUBLE FACTORS RELEASED BY ACTIVATED MACROPHAGES (CYTOTOXICITY, ELECTRON TRANSPORT, MONOCYTE)

Particular interest has been directed towards the macrophage as a primary antineoplastic cell due to its tumoricidal properties in vitro and the observation that an inverse relationship exists between the number of macrophages infiltrating a tumor and metastatic potential. The mechanism of macrophage-mediated injury of tumor cells remains unknown. Recently, it has been shown that injured tumor cells have defective mitochondrial respiration. Our studies have shown that activated macrophages can release soluble factors which can alter tumor cell respiration.^ The effects of a conditioned supernatant (CS) from cultures of activated macrophages on tumor cell (TC) mitochondrial respiration was studied. CS was obtained by incubation of BCG-elicited, murine peritoneal macrophage with RPMI-1640 supplemented with 10% FCS and 50 ng/ml bacterial endotoxin. This CS was used to treat cultures of EMT-6 TC for 24 hours. Mitochondrial respiration was measured polarigraphically using a Clark-type oxygen electrode. Cell growth rate was assessed by ('3)H-Thymidine incorporation. Exposure of EMT-6 TC to CS resulted in the inhibition of malate and succinate oxidation 76.6% and 72.9%, respectively. While cytochrome oxidase activity was decreased 61.1%. This inhibition was accompanied by a 98.8% inhibition of DNA synthesis (('3)H-Thymidine incorporation). Inhibition was dose-related with a 21.3% inhibition of succinate oxidase from a 0.3 ml dose of CS and a 50% inhibition with 1.0 mls. Chromatography of CS on Sephacryl S-200 resulted in isolation of an 80,000 and a 55,000 dalton component which contained the respiration inhibiting activity (RIF). These factors were distinct from a 120,000 dalton cytolytic factor determined by bioassay on Actinomycin-D treated L929 cells. RIF activity was also distinct from several other cytostatic factors but was itself associated with 2 peaks of cytostatic activity. Characterization of the RIF activity showed that it was destroyed by trypsin and heat (100(DEGREES)C, 5 min). It was stable over a broad range of pH (4-9) and its production was inhibited by cycloheximide. The RIF did not have a direct effect on isolated mitochondria of TC nor did it induce the formation of a stable intracellular toxin for mitochondria.^ In conclusion, activated macrophages synthesize and secrete an 80,000 and a 55,000 dalton protein which inhibits the mitochondrial metabolism of TC. These factors induce a cytostatic but not a cytolytic effect on TC.^ The macrophage plays a role in the control of normal and tumor cell growth and in tissue involution. Inhibition of respiration may be one mechanism used by macrophages to control cell growth.^

The heparan sulfate-fibroblast growth factor signaling system in liver growth and function

The heparan sulfate (HS)-fibroblast growth factor (FGF) signaling system is a ubiquitous regulator that senses local environmental changes and mediates cell-to-cell communication. This system consists of three mutually interactive components. These are regulatory polypeptides (FGF), FGF receptor (FGFR) and heparan sulfate proteoglycans (FGFRHS). All four FGFR genes are expressed in the adult liver. Expression of the FGFR1–3 genes is generally associated with non-parenchymal cells while expression of the FGFR4 gene is associated with parenchymal hepatocytes. We showed that livers of mice lacking FGFR4 exhibited normal morphology and regenerated normally in response to partial hepatectomy. However, the FGFR4 (−/−) mice exhibited depleted gallbladders, an elevated bile acid pool and elevated excretion of bile acids. Cholesterol- and bile acid-controlled liver cholesterol 7α-hydroxylase (Cyp7a), the limiting enzyme for bile acid synthesis, was elevated, unresponsive to dietary cholesterol, but repressed normally by dietary cholate. These results indicated that FGFR4 was not directly involved in liver growth but exerted negative control on liver bile acid synthesis. This was confirmed in transgenic mice overexpressing the constitutively active human FGFR4 in livers. The transgenic mice exhibited decreased fecal bile acid excretion, bile acid pool size, and expression of Cyp7a. Introduction of this constitutively active human FGFR4 into FGFR4 (−/−) mice restored the inhibition of bile acid synthesis. Activation of the c-Jun N-terminal Kinase (JNK) pathway by FGFR4 correlated with the repressive effect on bile acid synthesis. ^ To determine whether FGFR4 played a broader role in liver-specific metabolic function, we examined the impact of both acute and chronic exposure to CCl 4 in FGFR4 (−/−) mice. Following acute CCl4 exposure, the FGFR4 (−/−) mice exhibited accelerated liver injury, a significant increase in liver mass and delayed hepatolobular repair, with no apparent effect on liver cell proliferation and restoration of cellularity. Chronic CCl4 exposure resulted in severe fibrosis in livers of FGFR4 (−/−) mice compared to normal mice. Analysis at both mRNA and protein levels indicated an 8 hr delay in FGFR4-deficient mice in the down-regulation of cytochrome P450 2E1 (CYP2E1) protein, the major enzyme whose products underlie CCl 4-induced injury. These results show that hepatocyte FGFR4 protects against acute and chronic insult to the liver and prevents accompanying fibrosis. ^ Of the 23 FGF polypeptides, FGF1 and FGF2 are present at significant levels in the liver. To determine whether FGF1 and FGF2 played a role in CCl 4-induced liver injury and fibrosis, we examined the impact of both acute and chronic exposure to CCl4 in both wild-type and FGF1-FGF2 double-knockout mice. Following acute CCl4 exposure, FGF1(−/−)FGF2(−/−) mice exhibited accelerated liver injury, overall normal liver growth and repair, and decreased liver collagen α1(I) induction. Liver fibrosis resulting from chronic CCl4 exposure was markedly decreased in livers of FGF1(−/−)FGF2(−/−) mice compared to wild-type mice. This study suggests a role for FGF1 and FGF2 in hepatic fibrogenesis. ^ In summary, our three part study shows that specific components of the ubiquitous HS-FGF signaling family in the liver context interfaces with metabolite- and xenobiotic-controlled networks to regulate liver function, but has no apparent direct effect on liver cell growth. ^