A urokinase receptor promoter element (-152/-135) bound with an AP-2-alpha-related protein and SP1 is required for the induction of gene expression by PMA and SRC

The urokinase-type plasminogen activator receptor (u-PAR) promotes extracellular matrix degradation, invasion and metastasis. A first objective of this dissertation was to identify cis-elements and trans-acting factors activating u-PAR gene expression through a previously footprinted (–148/–124) promoter region. Mobility shifting experiments on nuclear extracts of a high u-PAR-expressing colon cancer cell line (RKO) indicated Sp1, Sp3 and a factor similar to, but distinct from, AP-2α bound to an oligonucleotide spanning –152/–135. Mutations preventing the binding of the AP-2α-related factor reduced u-PAR promoter activity. In RKO, the expression of a dominant negative AP-2 (AP-2αB) diminished u-PAR promoter activity, protein and u-PAR mediated laminin degradation. Conversely, u-PAR promoter activity in low u-PAR-expressing GEO cells was increased by AP-2αA expression. PMA treatment, which induces u-PAR expression, caused an increased amount of the AP-2α-related factor-containing complex in GEO, and mutations preventing AP-2α-like and Sp1/Sp3 binding reduced the u-PAR promoter stimulation by PMA. In resected colon cancers, u-PAR protein amounts were related to the amount of the AP-2α-related factor-containing complex. In conclusion, constitutive and PMA- inducible u-PAR gene expression and -proteolysis are mediated partly through transactivation via a promoter sequence (–152/435) bound with an AP-2α-related factor and Sp1/Sp3. ^ A second interest of this dissertation was to determine if a constitutively active Src regulates the transcription of the u-PAR gene, since c-src expression increases invasion in colon cancer. Increased u-PAR protein and laminin degradation paralleling elevated Src activity was evident in SW480 colon cancer cells stably expressing a constitutively active Src (Y- c-src527F). Nuclear run-on experiments indicated that this was due largely to transcriptional activation. While transient transfection of SW480 cells with Y-c-src527F induced a u-PAR-CAT-reporter, mutations preventing Sp1-binding to promoter region –152/435 abolished this induction. Mobility shift assays revealed increased Sp1 binding to region –152/135 with nuclear extracts of Src-transfected SW480 cells. Finally, the amounts of endogenous u-PAR in resected colon cancers significantly correlated with Src-activity. These data suggest that u-PAR gene expression and proteolysis are regulated by Src, this requiring the promoter region (–152/–135) bound with Sp1, thus, demonstrating for the first time that transcription factor Sp1 is a downstream effector of Src. ^

Respiratory-related leg movements and their relationship with periodic leg movements during sleep

STUDY OBJECTIVES: To describe the time structure of leg movements (LM) in obstructive sleep apnea (OSA) syndrome, in order to advance understanding of their clinical significance. LOCATION: Sleep Research Centre, Oasi Institute (IRCCS), Troina, Italy. SETTING: Sleep laboratory. PATIENTS: Eighty-four patients (16 females, 68 males, mean age 55.1 y, range 29-74 y). METHODS: Respiratory-related leg movements (RRLM) and those unrelated to respiratory events (NRLM) were examined within diagnostic polysomnograms alone and together for their distributions within the sleep period and for their periodicity. MEASUREMENTS AND RESULTS: Patients with OSA and RRLM exhibited more periodic leg movements in sleep (PLMS), particularly in NREM sleep. A gradual decrease in number of NRLM across the sleep period was observed in patients with RRLM. This pattern was less clear for RRLM. Frequency histograms of intermovement intervals of all LMs in patients with RRLM showed a prominent first peak at 4 sec, and a second peak at approximately 24 sec coincident with that of PLMS occurring in the absence of OSA. A third peak of lowest amplitude was the broadest with a maximum at approximately 42 sec. In patients lacking RRLM, NRLM were evident with a single peak at 2-4 sec. A stepwise linear regression analysis showed that, after controlling for a diagnosis of restless legs syndrome and apnea-hypopnea index, PLMS remained significantly associated with RRLM. CONCLUSION: The time structure of leg movements occurring in conjunction with respiratory events exhibit features of periodic leg movements in sleep occurring alone, only with a different and longer period. This brings into question the validity, both biologic and clinical, of scoring conventions with their a priori exclusion from consideration as periodic leg movements in sleep.

CAP Reform vs WTO: Crop Diversification or Crop Rotation? : Legal opinion prepared by Dr. Christian Häberli at the request of APRODEV, the Association of World Council of Churches related Development Organisations in Europe

The European Commission’s proposals for the Legislative Framework of the Common Agricultural Policy (CAP) in the period 2014-2020 include, inter alia, the introduction of a “strong greening component”. For the first time, all EU farmers in receipt of support are to “go beyond the requirements of cross compliance and deliver environmental and climate benefits as part of their everyday activities crop diversification as a contribution to all EU farmers in receipt of support go beyond the requirements of cross compliance and deliver environmental and climate benefits as part of their everyday activities.” In a legal opinion prepared at the request of APRODEV, the Association of World Council of Churches related Development Organisations in Europe (www.aprodev.eu), Christian Häberli examines the WTO implications of this proposal, as compared with an alternative proposal to rather link direct payments to crop rotation. The conclusions are twofold: 1. Crop rotation is at least as likely to be found Green Box-compatible as crop diversification. Moreover, it will be more difficult to argue that crop diversification is “not more than minimally production-distorting” because it entails for most farmers less cost and work. 2. Even if (either of the two cropping schemes) were to be found “amber”, the EU would not have to relinquish this conditionality. This is because the direct payments involved would in all likelihood not, together with the other price support instruments, exceed the amount available under the presently scheduled maximum.

Manipulations to reduce simulator-related transient adverse health effects during simulated driving

User comfort during simulated driving is of key importance, since reduced comfort can confound the experiment and increase dropout rates. A common comfort-affecting factor is simulator-related transient adverse health effect (SHE). In this study, we propose and evaluate methods to adapt a virtual driving scene to reduce SHEs. In contrast to the manufacturer-provided high-sensory conflict scene (high-SCS), we developed a low-sensory conflict scene (low-SCS). Twenty young, healthy participants drove in both the high-SCS and the low-SCS scene for 10 min on two different days (same time of day, randomized order). Before and after driving, participants rated SHEs by completing the Simulator Sickness Questionnaire (SSQ). During driving, several physiological parameters were recorded. After driving in the high-SCS, the SSQ score increased in average by 129.4 (122.9 %, p = 0.002) compared to an increase of 5.0 (3.4 %, p = 0.878) after driving in the low-SCS. In the low-SCS, skin conductance decreased by 13.8 % (p < 0.01) and saccade amplitudes increased by 16.1 % (p < 0.01). Results show that the investigated methods reduce SHEs in a younger population, and the low-SCS is well accepted by the users. We expect that these measures will improve user comfort.

Time for actions in lucid dreams: effects of task modality, length, and complexity

The relationship between time in dreams and real time has intrigued scientists for centuries. The question if actions in dreams take the same time as in wakefulness can be tested by using lucid dreams where the dreamer is able to mark time intervals with prearranged eye movements that can be objectively identified in EOG recordings. Previous research showed an equivalence of time for counting in lucid dreams and in wakefulness (LaBerge, 1985; Erlacher and Schredl, 2004), but Erlacher and Schredl (2004) found that performing squats required about 40% more time in lucid dreams than in the waking state. To find out if the task modality, the task length, or the task complexity results in prolonged times in lucid dreams, an experiment with three different conditions was conducted. In the first condition, five proficient lucid dreamers spent one to three non-consecutive nights in the sleep laboratory. Participants counted to 10, 20, and 30 in wakefulness and in their lucid dreams. Lucidity and task intervals were time stamped with left-right-left-right eye movements. The same procedure was used for these condition where eight lucid dreamers had to walk 10, 20, or 30 steps. In the third condition, eight lucid dreamers performed a gymnastics routine, which in the waking state lasted the same time as walking 10 steps. Again, we found that performing a motor task in a lucid dream requires more time than in wakefulness. Longer durations in the dream state were present for all three tasks, but significant differences were found only for the tasks with motor activity (walking and gymnastics). However, no difference was found for relative times (no disproportional time effects) and a more complex motor task did not result in more prolonged times. Longer durations in lucid dreams might be related to the lack of muscular feedback or slower neural processing during REM sleep. Future studies should explore factors that might be associated with prolonged durations.

A relation between screening masses and real-time rates

Thermal screening masses related to the conserved vector current are determined for the case that the current carries a non-zero Matsubara frequency, both in a weak-coupling approach and through lattice QCD. We point out that such screening masses are sensitive to the same infrared physics as light-cone real-time rates. In particular, on the perturbative side, the inhomogeneous Schrödinger equation determining screening correlators is shown to have the same general form as the equation implementing LPM resummation for the soft-dilepton and photon production rates from a hot QCD plasma. The static potential appearing in the equation is identical to that whose soft part has been determined up to NLO and on the lattice in the context of jet quenching. Numerical results based on this potential suggest that screening masses overshoot the free results (multiples of 2πT) more strongly than at zero Matsubara frequency. Four-dimensional lattice simulations in two-flavour QCD at temperatures of 250 and 340 MeV confirm the non-static screening masses at the 10% level. Overall our results lend support to studies of jet quenching based on the same potential at T ≳ 250 MeV.

Studying changes in life circumstances and personality: It's about time

Most theories of personality development posit that changes in life circumstances (e.g. due to major life events) can lead to changes in personality, but few studies have examined the exact time course of these changes. In this article, we argue that time needs to be considered explicitly in theories and empirical studies on personality development. We discuss six notions on the role of time in personality development. First, people can differ before the event. Second, change can be non-linear and discontinuous. Third, change can be reversible. Fourth, change can occur before the event. Fifth, control groups are needed to disentangle age-related and event-related changes. Sixth, we need to move beyond examining single major life events and study the effects of non-normative events, non-events, multiple events, and minor events on personality. We conclude by summarizing the methodological and theoretical implications of these notions.

Endogenous α-calcitonin-gene-related peptide promotes exercise-induced, physiological heart hypertrophy in mice.

AIM It is unknown how the heart distinguishes various overloads, such as exercise or hypertension, causing either physiological or pathological hypertrophy. We hypothesize that alpha-calcitonin-gene-related peptide (αCGRP), known to be released from contracting skeletal muscles, is key at this remodelling. METHODS The hypertrophic effect of αCGRP was measured in vitro (cultured cardiac myocytes) and in vivo (magnetic resonance imaging) in mice. Exercise performance was assessed by determination of maximum oxygen consumption and time to exhaustion. Cardiac phenotype was defined by transcriptional analysis, cardiac histology and morphometry. Finally, we measured spontaneous activity, body fat content, blood volume, haemoglobin mass and skeletal muscle capillarization and fibre composition. RESULTS While αCGRP exposure yielded larger cultured cardiac myocytes, exercise-induced heart hypertrophy was completely abrogated by treatment with the peptide antagonist CGRP(8-37). Exercise performance was attenuated in αCGRP(-/-) mice or CGRP(8-37) treated wild-type mice but improved in animals with higher density of cardiac CGRP receptors (CLR-tg). Spontaneous activity, body fat content, blood volume, haemoglobin mass, muscle capillarization and fibre composition were unaffected, whereas heart index and ventricular myocyte volume were reduced in αCGRP(-/-) mice and elevated in CLR-tg. Transcriptional changes seen in αCGRP(-/-) (but not CLR-tg) hearts resembled maladaptive cardiac phenotype. CONCLUSIONS Alpha-calcitonin-gene-related peptide released by skeletal muscles during exercise is a hitherto unrecognized effector directing the strained heart into physiological instead of pathological adaptation. Thus, αCGRP agonists might be beneficial in heart failure patients.

VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children

BACKGROUND Despite substantial evidence supporting a pharmacogenetic approach to warfarin therapy in adults, evidence on the importance of genetics in warfarin therapy in children is limited, particularly for clinical outcomes. We assessed the contribution of CYP2C9/VKORC1/CYP4F2 genotypes and variation in other genes involved in vitamin K and coagulation pathways to warfarin dose and related clinical outcomes in children. PROCEDURE Clinical and genetic data for 93 children (age ≤ 18 years) who received warfarin therapy were obtained. DNA was genotyped for 93 selected single nucleotide polymorphisms using a custom assay. RESULTS With a median age of 4.8 years, our cohort included more young children than most previous studies. Overall, 76.3% of dose variability was explained by weight, indication, VKORC1-1639G/A and CYP2C9 *2/*3, with genotypes accounting for 21.1% of variability. There was a strong correlation (R(2) = 0.68; P < 0.001) between actual and predicted warfarin dose using a pediatric genotype-based dosing model. VKORC1 genotype had a significant impact on time to therapeutic international normalized ratio (INR) (P = 0.047) and time to over-anticoagulation (INR > 4; P = 0.024) during the initiation of therapy. CYP2C9*3 carriers were also at increased risk of major bleeding while receiving warfarin (adjusted OR = 11.28). An additional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose (P = 0.020) in a multivariate clinical and genetic model. CONCLUSIONS This study confirms the importance of VKORC1/CYP2C9 genotypes for warfarin dosing in a young pediatric cohort and demonstrates an impact of genetic factors on clinical outcomes in children. Furthermore, we identified an additional variant in CYP2C9 of potential relevance for warfarin dosing in children.

The effect of ego depletion on sprint start reaction time

In the current study, we consider that optimal sprint start performance requires the self-control of responses. Therefore, start performance should depend on athletes' self-control strength. We assumed that momentary depletion of self-control strength (ego depletion) would either speed up or slow down the initiation of a sprint start, where an initiation that was sped up would carry the increased risk of a false start. Applying a mixed between- (depletion vs. nondepletion) and within- (before vs. after manipulation of depletion) subjects design, we tested the start reaction times of 37 sport students. We found that participants' start reaction times decelerated after finishing a depleting task, whereas it remained constant in the nondepletion condition. These results indicate that sprint start performance can be impaired by unrelated preceding actions that lower momentary self-control strength. We discuss practical implications in terms of optimizing sprint starts and related overall sprint performance.

Return to Work after Traumatic Hand Injuries: Medical, Personal and Work-related Factors

PURPOSE This study aimed to examine the work-related impact of open hand injuries, specifically, the amount of lost work days subsequent to the injury and factors associated with work-related rehabilitation. PATIENTS AND METHODS We retrospectivley included consecutive patients with acute hand injuries who were operated between 2008 and 2009 in the Division of Hand Surgery (n=435) at the Department of Orthopaedic, Plastic and Hand Surgery. Information was obtained from the medical records and via a self-reported questionnaire sent out in 2011. Patients younger than 18 or older than 65 years, as well as the unemployed were excluded from the study. Descriptive group analysis was used to establish statistical relationships between time off work (TOW) and possible influencing variables. Multiple linear regression was applied to analyse the impact of injury, personal and/or work-related factors on TOW. RESULTS The sample included 290 patients with a mean age of 38.9 (SD 13.2) years of whom 98.6% returned to work after a median absence of 45.5 days. Univariate analysis demonstrated an association of length of absence from work with socio-demographic, clinical and work-related factors. Multiple regression analysis indicated that the location of injury, the number of injured regions, the need for secondary surgery, age, and the type of occupation were independently associated with TOW. CONCLUSION Most factors associated with TOW after traumatic hand injuries could not be influenced. Possible interventions should probably target improved injury prevention, optimal clinical treatment and rehabilitation starting early after injury. Whether improvements in communication and enhancement of cooperation between the treatment teams, the workplace and the insurance carrier may support a staged and earlier return to work remains to be investigated.

Is intracranial aneurysm rupture related to solar activity?

Objective: A number of intrinsic and extrinsic risk factors for the rupture of intracranial aneurysms have been identified. Still, the cause precipitating aneurysm rupture remains unknown in many cases. In addition, it has been observed that aneurysm ruptures are clustered in time but the trigger mechanism remains obscure. As solar activity has been associated with cardiovascular mortality and morbidity we decided to study ist association to aneurysm rupture in the Swiss population. Method: Patient data was extracted from the Swiss SOS database, at time of analysis covering 918 patients with angiography-proven aSAH treated at seven Swiss neurovascular centers between 01/01/2009 – 12/31/2011. The number of aneurysm rupture per day, week, month (Daily/Weekly/Monthly Rupture Frequency = RF) was measured and correlated to the absolute amount and the change in various parameters of interest representing continuous measurements of solar activity (radioflux (F10.7 index), solar proton flux, solar flare occurrence, planetary K-index/planetary A-index) using Poisson regression analysis. Results: Of a consecutive series of 918 cases of SAH, precise determination of the date of symptom onset was possible in 816 (88.9%). During the period of interest there were 517 days without recorded aneurysm rupture. There were 398, 139, 27 and 12 days with 1, 2, 3, and 4 ruptures per day. Five or 6 ruptures were only noted on a single day each. Poisson regression analysis demonstrated a significant correlation of F10.7 index and aneurysm rupture (incidence rate ratio (IRR) = 1.006303; standard error (SE) 0.0013201; 95% confidence interval (CI) 1.003719 – 1.008894; p<0.001), according to which every 1-unit increase of the F10.7 index increased the count for an aneurysm to rupture by 0.63%. As the F10.7 index is known to correlate well with the Space Environment Services Center (SESC) sunspot number, we performed additional analyses on SESC sunspot number and sunspot area. Here, a likewise statistically significant relationship of both the SESC sunspot number (IRR 1.003413; SE 0.0007913; 95%CI 1.001864 – 1.004965; p<0.001) and the sunspot area (IRR 1.000419; SE 0.0000866; 95%CI 1.000249 – 1.000589; p<0.001) emerged. All other variables analyzed showed no correlation with RF. Conclusions: Using valid methods, we found higher radioflux, sunspot number and sunspot area to be associated with an increased count of aneurysm rupture. Since we were using rupture frequencies rather than incidences and because we cannot explain the physiological basis of this statistical association, the clinical meaningfulness of this statistical association must be interpreted carefully. Future studies are warranted to rule out a type-1 error.

The effect of age and time perspective on implicit motives

People differ in how open-ended or limited they perceive their future. We argue that individual differences in future time perspective affect the activation of implicit motives. Perceiving the time remaining for the satisfaction of one’s motives as limited should be associated with a higher activation of these motives than perceiving one’s future as more open-ended. Given that future time perspective decreases across adulthood, older adults should score higher on implicit motives than younger adults. This hypothesis was supported in a study with young (n = 53, age M = 25.60 years) and older adults (n = 55, age M = 68.05 years). Additionally, an experimental manipulation of future time perspective showed that age-related differences in implicit motives are influenced by future time perspective. These findings demonstrate that future time perspective is an important factor to explain the strength of motives.

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand on NK Cells Protects From Hepatic Ischemia-Reperfusion Injury

BACKGROUND: Ischemia-reperfusion injury (IRI) significantly contributes to graft dysfunction after liver transplantation. Natural killer (NK) cells are crucial innate effector cells in the liver and express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent inducer of hepatocyte cell death. Here, we investigated if TRAIL expression on NK cells contributes to hepatic IRI. METHODS: The outcome after partial hepatic IRI was assessed in TRAIL-null mice and contrasted to C57BL/6J wild-type mice and after NK cell adoptive transfer in RAG2/common gamma-null mice that lack T, B, and NK cells. Liver IRI was assessed by histological analysis, alanine aminotransferase, hepatic neutrophil activation by myeloperoxidase activity, and cytokine secretion at specific time points. NK cell cytotoxicity and differentiation were assessed in vivo and in vitro. RESULTS: Twenty-four hours after reperfusion, TRAIL-null mice exhibited significantly higher serum transaminases, histological signs of necrosis, neutrophil infiltration, and serum levels of interleukin-6 compared to wild-type animals. Adoptive transfer of TRAIL-null NK cells into immunodeficient RAG2/common gamma-null mice was associated with significantly elevated liver damage compared to transfer of wild-type NK cells. In TRAIL-null mice, NK cells exhibit higher cytotoxicity and decreased differentiation compared to wild-type mice. In vitro, cytotoxicity against YAC-1 and secretion of interferon gamma by TRAIL-null NK cells were significantly increased compared to wild-type controls. CONCLUSIONS: These experiments reveal that expression of TRAIL on NK cells is protective in a murine model of hepatic IRI through modulation of NK cell cytotoxicity and NK cell differentiation.