A. Pfeiffer

Geant4 is a toolkit for simulating the passage of particles through matter. It includes a complete range of functionality including tracking, geometry, physics models and hits. The physics processes offered cover a comprehensive range, including electromagnetic, hadronic and optical processes, a large set of long-lived particles, materials and elements, over a wide energy range starting, in some cases, from 250eV and extending in others to the TeV energy range. It has been designed and constructed to expose the physics models utilised, to handle complex geometries, and to enable its easy adaptation for optimal use in different sets of applications. The toolkit is the result of a worldwide collaboration of physicists and software engineers. It has been created exploiting software engineering and object-oriented technology and implemented in the C++ programming language. It has been used in applications in particle physics, nuclear physics, accelerator design, space engineering and medical physics.

Geant4 is a software toolkit for the simulation of the passage of particles through matter. It is used by a large number of experiments and projects in a variety of application domains, including high energy physics, astrophysics and space science, medical physics and radiation protection. Its functionality and modeling capabilities continue to be extended, while its performance is enhanced. An overview of recent developments in diverse areas of the toolkit is presented. These include performance optimization for complex setups; improvements for the propagation in fields; new options for event biasing; and additions and improvements in geometry, physics processes and interactive capabilities

There is increasing evidence of genetic factors leading to obesity, but the exact genes involved have not been defined. Peroxisome-proliferator-activated receptor gamma2 (PPARgamma2) is a transcription factor that has a key role in adipocyte differentiation, and therefore mutations of the gene for this factor might predispose people to obesity.We studied 358 unrelated German subjects, including 121 obese subjects (defined as those with a body-mass index [the weight in kilograms divided by the square of the height in meters] of more than 29). We evaluated these subjects for mutations in the gene for PPARgamma2 at or near a site of serine phosphorylation at position 114 that negatively regulates the transcriptional activity of the protein, using a polymerase-chain-reaction-based assay coupled with specific endonuclease digestion. The activity of the mutation identified was analyzed by retroviral transfection and overexpression in murine fibroblasts.Four of the 121 obese subjects had a missense mutation in the gene for PPARgamma2 that resulted in the conversion of proline to glutamine at position 115, as compared with none of the 237 subjects of normal weight (P=0.01). All the subjects with the mutant allele were markedly obese, with body-mass-index values ranging from 37.9 to 47.3, as compared with a mean of 33.6 in the other obese subjects. Overexpression of the mutant gene in murine fibroblasts led to the production of a protein in which the phosphorylation of serine at position 114 was defective, as well as to accelerated differentiation of the cells into adipocytes and greater cellular accumulation of triglyceride than with the wild-type PPARgamma2. These effects were similar to those of an in vitro mutation created directly at the Ser114 phosphorylation site.A Pro115Gln mutation in PPARgamma2 accelerates the differentiation of adipocytes and may cause obesity.

We report on measurements of low-mass electron pairs in 450 GeV p-Be, p-Au, and 200 GeV/nucleon S-Au collisions at central rapidities. For the proton induced interactions, the low-mass spectra are, within the systematic errors, satisfactorily explained by electron pairs from hadron decays, whereas in the S-Au system an enhancement over the hadronic contributions by a factor of 5.0±0.7(stat)±2.0(syst) in the invariant mass range 0.2<m<1.5GeV/c2 is observed. The properties of the excess suggest that it arises from two-pion annihilation ππ→e+e−.Received 2 March 1995DOI:https://doi.org/10.1103/PhysRevLett.75.1272©1995 American Physical Society

Diabetes management relies on effective evidence-based advice that informs and empowers individuals to manage their health. Alongside other cornerstones of diabetes management, dietary advice has the potential to improve glycaemic levels, reduce risk of diabetes complications and improve health-related quality of life. We have updated the 2004 recommendations for the nutritional management of diabetes to provide health professionals with evidence-based guidelines to inform discussions with patients on diabetes management, including type 2 diabetes prevention and remission. To provide this update we commissioned new systematic reviews and meta-analyses on key topics, and drew on the broader evidence available. We have strengthened and expanded on the previous recommendations to include advice relating to dietary patterns, environmental sustainability, food processing, patient support and remission of type 2 diabetes. We have used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach to determine the certainty of evidence for each recommendation based on findings from the commissioned and identified systematic reviews. Our findings indicate that a range of foods and dietary patterns are suitable for diabetes management, with key recommendations for people with diabetes being largely similar for those for the general population. Important messages are to consume minimally processed plant foods, such as whole grains, vegetables, whole fruit, legumes, nuts, seeds and non-hydrogenated non-tropical vegetable oils, while minimising the consumption of red and processed meats, sodium, sugar-sweetened beverages and refined grains. The updated recommendations reflect the current evidence base and, if adhered to, will improve patient outcomes.

We report a measurement of low-mass electron pairs observed in 158 GeV/nucleon Pb-Au collisions. The pair yield integrated over the range of invariant masses 0.2 ≤m≤ 2.0 GeV/c2 is enhanced by a factor of 3.5 ± 0.4 (stat) ± 0.9 (syst) over the expectation from neutral meson decays. As observed previously in S-Au collisions, the enhancement is most pronounced in the invariant-mass region 300-700 MeV/c2. For Pb-Au we find evidence for a strong increase of the enhancement with centrality. In addition, we show that the enhancement covers a wide range in transverse momentum, but is largest at the lowest observed p⊥.

When we ask people what they value most, health is usually top of the list. While effective care is available for many chronic diseases, the fact remains that for the patient, the tax payer and the whole of society: prevention is better than cure. Diabetes and its complications are a serious threat to the survival and well-being of an increasing number of people. It is predicted that one in ten Europeans aged 20-79 will have developed diabetes by 2030. Once a disease of old age, diabetes is now common among adults of all ages and is beginning to affect adolescents and even children. Diabetes accounts for up to 18 % of total healthcare expenditure in Europe. The good news is that diabetes is preventable. Compelling evidence shows that the onset of diabetes can be prevented or delayed greatly in individuals at high risk (people with impaired glucose regulation). Clinical research has shown a reduction in risk of developing diabetes of over 50 % following relatively modest changes in lifestyle that include adopting a healthy diet, increasing physical activity, and maintaining a healthy body weight. These results have since been reproduced in real-world prevention programmes. Even a delay of a few years in the progression to diabetes is expected to reduce diabetes-related complications, such as heart, kidney and eye disease and, consequently, to reduce the cost to society. A comprehensive approach to diabetes prevention should combine population based primary prevention with programmes targeted at those who are at high risk. This approach should take account of the local circumstances and diversity within modern society (e.g. social inequalities). The challenge goes beyond the healthcare system. We need to encourage collaboration across many different sectors: education providers, non-governmental organisations, the food industry, the media, urban planners and politicians all have a very important role to play. Small changes in lifestyle will bring big changes in health. Through joint efforts, more people will be reached. The time to act is now.

Adiponectin has recently been reported to generate a negative energy balance by increasing energy expenditure. However, it is unclear whether such effects require the presence and direct action of the adiponectin protein in the central nervous system. In this study, neither radiolabeled nonglycosylated nor glycosylated globular adiponectin crossed the blood-brain barrier (BBB) in mice. In addition, adiponectin was not detectable in human cerebrospinal fluid using various established methods. Using murine cerebral microvessels, we demonstrated expression of adiponectin receptors, which are upregulated during fasting, in brain endothelium. Interestingly, treatment with adiponectin reduced secretion of the centrally active interleukin-6 from brain endothelial cells, a phenomenon that was paralleled by a similar trend of other proinflammatory cytokines. In summary, our data suggest that direct effects of endogenous adiponectin on central nervous system pathways are unlikely to exist. However, the identification of adiponectin receptors on brain endothelial cells and the finding of a modified secretion pattern of centrally active substances from BBB cells provides an alternate explanation as to how adiponectin may evoke effects on energy metabolism.

Reduced telomere length and impaired telomerase activity have been linked to several diseases associated with senescence and aging. However, a causal link to metabolic disorders and in particular diabetes mellitus is pending. We here show that young adult mice which are deficient for the Terc subunit of telomerase exhibit impaired glucose tolerance. This is caused by impaired glucose-stimulated insulin secretion (GSIS) from pancreatic islets, while body fat content, energy expenditure and insulin sensitivity were found to be unaltered. The impaired secretion capacity for insulin is due to reduced islet size which is linked to an impaired replication capacity of insulin-producing beta-cells in Terc-deficient mice. Taken together, telomerase deficiency and hence short telomeres impair replicative capacity of pancreatic beta-cells to cause impaired insulin secretion and glucose intolerance, mechanistically defining diabetes mellitus as an aging-associated disorder.

Remission of type 2 diabetes can occur as a result of weight loss and is characterised by liver fat and pancreas fat reduction and recovered insulin secretion. In this analysis, we aimed to investigate the mechanisms of weight loss- induced remission in people with prediabetes.In this prespecified post-hoc analysis, weight loss-induced resolution of prediabetes in the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS) was assessed, and the results were validated against participants from the Diabetes Prevention Program (DPP) study. For PLIS, between March 1, 2012, and Aug 31, 2016, participants were recruited from eight clinical study centres (including seven university hospitals) in Germany and randomly assigned to receive either a control intervention, a standard lifestyle intervention (ie, DPP-based intervention), or an intensified lifestyle intervention for 12 months. For DPP, participants were recruited from 23 clinical study centres in the USA between July 31, 1996, and May 18, 1999, and randomly assigned to receive either a standard lifestyle intervention, metformin, or placebo. In both PLIS and DPP, only participants who were randomly assigned to receive lifestyle intervention or placebo and who lost at least 5% of their bodyweight were included in this analysis. Responders were defined as people who returned to normal fasting plasma glucose (FPG; <5·6 mmol/L), normal glucose tolerance (<7·8 mmol/L), and HbA1c less than 39 mmol/mol after 12 months of lifestyle intervention or placebo or control intervention. Non-responders were defined as people who had FPG, 2 h glucose, or HbA1c more than these thresholds. The main outcomes for this analysis were insulin sensitivity, insulin secretion, visceral adipose tissue (VAT), and intrahepatic lipid content (IHL) and were evaluated via linear mixed models.Of 1160 participants recruited to PLIS, 298 (25·7%) had weight loss of 5% or more of their bodyweight at baseline. 128 (43%) of 298 participants were responders and 170 (57%) were non-responders. Responders were younger than non-responders (mean age 55·6 years [SD 9·9] vs 60·4 years [8·6]; p<0·0001). The DPP validation cohort included 683 participants who lost at least 5% of their bodyweight at baseline. Of these, 132 (19%) were responders and 551 (81%) were non-responders. In PLIS, BMI reduction was similar between responders and non-responders (responders mean at baseline 32·4 kg/m2 [SD 5·6] to mean at 12 months 29·0 kg/m2 [4·9] vs non-responders 32·1 kg/m2 [5·9] to 29·2 kg/m2 [5·4]; p=0·86). However, whole-body insulin sensitivity increased more in responders than in non-responders (mean at baseline 291 mL/[min × m2], SD 60 to mean at 12 months 378 mL/[min × m2], 56 vs 278 mL/[min × m2], 62, to 323 mL/[min × m2], 66; p<0·0001), whereas insulin secretion did not differ within groups over time or between groups (responders mean at baseline 175 pmol/mmol [SD 64] to mean at 12 months 163·7 pmol/mmol [60·6] vs non-responders 158·0 pmol/mmol [55·6] to 154·1 pmol/mmol [56·2]; p=0·46). IHL decreased in both groups, without a difference between groups (responders mean at baseline 10·1% [SD 8·7] to mean at 12 months 3·5% [3·9] vs non-responders 10·3% [8·1] to 4·2% [4·2]; p=0·34); however, VAT decreased more in responders than in non-responders (mean at baseline 6·2 L [SD 2·9] to mean at 12 months 4·1 L [2·3] vs 5·7 L [2·3] to 4·5 L [2·2]; p=0·0003). Responders had a 73% lower risk of developing type 2 diabetes than non-responders in the 2 years after the intervention ended.By contrast to remission of type 2 diabetes, resolution of prediabetes was characterised by an improvement in insulin sensitivity and reduced VAT. Because return to normal glucose regulation (NGR) prevents development of type 2 diabetes, we propose the concept of remission of prediabetes in analogy to type 2 diabetes. We suggest that remission of prediabetes should be the primary therapeutic aim in individuals with prediabetes.German Federal Ministry for Education and Research via the German Center for Diabetes Research; the Ministry of Science, Research and the Arts Baden-Württemberg; the Helmholtz Association and Helmholtz Munich; the Cluster of Excellence Controlling Microbes to Fight Infections; and the German Research Foundation.

Abstract. Hyperglycemia-induced overproduction of the prosclerotic cytokine transforming growth factor-β1 (TGF-β1) has been implicated in the pathogenesis of diabetic nephropathy. Because high glucose and phorbol esters (PMA) increase TGF-β1 mRNA levels in mesangial cells, this study was designed to characterize these effects on the human TGF-β1 promoter activity. With the use of luciferase reporter gene constructs containing TGF-β1 5′-flanking sequence (from -453 to +11 bp) transfected into mesangial cells, it was found that 30 mM glucose induced a nearly twofold increase in TGF-β1 promoter activity after 24 h of incubation in human and porcine mesangial cells. Stimulation by PMA was more effective (2.3-fold). Mutagenesis in either one of the two or both activating protein-1 (AP-1) binding sites abolished the high glucose and the PMA effect. Furthermore, addition of the AP-1 inhibitor curcumin obliterated the glucose response. Corresponding experiments revealed that the transcription factor stimulating protein 1 was not involved in mediating the glucose effect. The high glucose-induced TGF-β1 promoter activation was also prevented by inhibitors of protein kinase C and p38 mitogen-activated proteinkinase. Electrophoretic mobility shift assays with oligonucleotides containing one of the two AP-1 binding sites showed that glucose treatment markedly enhanced the binding activity of nuclear proteins of mesangial cells, particularly to box B. Supershift assays demonstrated that JunD and c-Fos were present in the protein-DNA complexes under control and hyperglycemic conditions. The functional and structural results show that glucose regulates human TGF-β1 gene expression through two adjacent AP-1 binding sites and gives rise to the involvement of protein kinase C and p38 mitogen-activated proteinkinase in hyperglycemia-induced TGF-β1 gene expression.

We report on first measurements of low-mass electron-positron pairs in Pb-Au collisions at the CERN SPS beam energy of 40 AGeV. The observed pair yield integrated over the range of invariant masses 0.2<m</=1 GeV/c(2) is enhanced over the expectation from neutral meson decays by a factor of 5.9+/-1.5(stat)+/-1.2(syst data)+/-1.8(syst meson decays), somewhat larger than previously observed at the higher energy of 158 AGeV. The results are discussed with reference to model calculations based on pi(+)pi(-)-->e(+)e(-) annihilation with a modified rho propagator. They may be linked to chiral symmetry restoration and support the notion that the in-medium modifications of the rho are more driven by baryon density than by temperature.

Measurements of event-by-event fluctuations of the mean transverse momentum in Pb-Au collisions at 40, 80, and 158 A GeV/c are presented. A significant excess of mean p_T fluctuations at mid-rapidity is observed over the expectation from statistically independent particle emission. The results are somewhat smaller than recent measurements at RHIC. A possible non-monotonic behaviour of the mean p_T fluctuations as function of collision energy, which may have indicated that the system has passed the critical point of the QCD phase diagram in the range of mu_B under investigation, has not been observed. The centrality dependence of mean p_T fluctuations in Pb-Au is consistent with an extrapolation from pp collisions assuming that the non-statistical fluctuations scale with multiplicity. The results are compared to calculations by the RQMD and UrQMD event generators.

The clinical implications of the epidermal growth factor (EGF) and its receptor (EGF-R) were studied in 52 squamous cell carcinomas of the uterine cervix. In comparison to 40 biopsies of the normal cervix EGF-R capacity was significantly increased in the carcinomas, while the affinity was unchanged. The amount of EGF-like substances extracted from the tumors was increased in patients with lymph node metastases, in whom 5-year survival is reduced. Irrespective of tumor stage patients with a very high level of EGF-R (>100 fmole/mg protein) were more likely to have recurrences later or to die from disease: recurrence or death occurred in 5 of 7 patients with high capacity and in 2 of 45 patients with low capacity. Our data suggest that the level of EGF-R is indicative of the biological aggressiveness of cervical carcinomas.

We present a measurement of e+e− pair production in central PbAu collisions at 158AGeV/c. As reported earlier, a significant excess of the e+e− pair yield over the expectation from hadron decays is observed. The improved mass resolution of the present data set, recorded with the upgraded CERES experiment at the CERN-SPS, allows for a comparison of the data with different theoretical approaches. The data clearly favor a substantial in-medium broadening of the ρ spectral function over a density-dependent shift of the ρ pole mass. The in-medium broadening model implies that baryon induced interactions are the key mechanism to the observed modifications of the ρ meson at SPS energy.

Biocoke has the potential to reduce the fossil-based materials in metallurgical processes, along with mitigating anthropogenic CO2- and greenhouse gas (GHG) emissions. Reducing those emissions is possible by using bio-based carbon, which is CO2-neutral, as a partial replacement of fossil carbon. In this paper, the effect of adding 5, 10, 15, 30, and 45 wt.% biomass pellets on the reactivity, the physicomechanical, and electrical properties of biocoke was established to assess the possibility of using it as a fuel and reducing agent for a blast furnace (BF) or as a carbon source in a submerged arc furnace (SAF). Biocoke was obtained under laboratory conditions at final coking temperatures of 950 or 1100 °C. Research results indicate that for BF purposes, 5 wt.% biomass additives are the maximum as the reactivity increases and the strength after reaction with CO2 decreases. On the other hand, biocoke's physicomechanical and electrical properties, obtained at a carbonization temperature of 950 °C, can be considered a promising option for the SAF.

Adding 5 mass% wood pellets in a coal blend affects the reactivity with CO2 and microstructural properties of the coke at different final coking temperatures of 950 and 1100 °C. A correlation between coke reactivity index (CRI) and BET specific surface area was found. The reactivity of coke and biocoke decreases with a decrease in the specific surface area, as well as with an increase in the carbonization temperature. Raman spectroscopy results indicate that the higher carbonization temperature of biocoke mitigates the effect of 5 mass% of biomass addition. The X-ray diffraction-based interlayer spacing of carbon crystallite (d002) decreases slightly with increasing carbonization temperature, and crystallite height (Lc) increases with rising coking temperature for both coke and biocoke. Additionally, the lower the d002 value, the lower the CRI of the cokes and biocokes. A good correlation between CRI and d002 is observed. Carbon crystallite width (La) values increased with a rising carbonization temperature, indicating the intensive growth of carbon crystallites in all directions. However, these values for biocokes are lower due to the presence of charcoal particles.

Statistical methods play a significant role throughout the life-cycle of physics experiments, being an essential component of physics analysis. The present project in progress aims to develop an object-oriented software Toolkit for statistical data analysis. The Toolkit contains a variety of Goodness-of-Fit (GoF) tests, from Chi-squared to Kolmogorov-Smirnov, to less known, but generally much more powerful tests such as Anderson-Darling, Goodman, Fisz-Cramer-von Mises, Kuiper. Thanks to the component-based design and the usage of the standard abstract interfaces for data analysis, this tool can be used by other data analysis systems or integrated in experimental software frameworks. In this paper we describe the statistical details of the algorithms and the computational features of the Toolkit. With the aim of showing the consistency between the code and the mathematical features of the algorithms, we describe the results we obtained reproducing by means of the Toolkit a couple of Goodness-of-Fit testing examples of relevance in statistics literature.

Chronic hyperglycemia may cause growth factor alterations that are likely to participate in tissue remodeling typical for diabetic late complications. However, few details of such events are known. The ocular vitreous fluid allows studies of growth factor levels in human eyes (after vitrectomy). The vitreous is highly inert and protected by the blood-retina barrier and thus probably reflects growth factor production by the normal retina. Vitreous from patients with proliferative diabetic retinopathy (PDR) was compared with vitreous obtained from patients with nonproliferative eye disease and with vitreous from patients without diabetes but with marked neovascular proliferations due to ischemia. This design permits us to distinguish diabetes-related from non-diabetes-related alterations. Insulin-like growth factor I (IGF-I), IGF-II, IGF binding protein 2 (IGFBP-2), and IGFBP-3 were elevated 3-to 13-fold in nondiabetic retinal ischemia and 1.5- to 3-fold in PDR, indicating that the changes were not restricted to diabetes. These changes may partially be explained by leakage of serum into the vitreous, since IGFs and IGFBPs are 20- to 50-fold higher in serum than in vitreous, and vitreous protein content was 1.5-fold elevated in PDR subjects and 5-fold in ischemia patients compared with control subjects. TGF-β is a proposed antiangiogenic factor in the eye. TGF-β2 was the predominant subtype in vitreous, and its total amount was not altered in PDR patients. More importantly, the active fraction of TGF-β was decreased by 30 and 70% in PDR and nondiabetic retinal ischemia patients, respectively. Since plasmin may control TGF-β activation, the serum protein α2-antiplasmin was measured and found to be significantly elevated to 150 and 250% of control values in PDR and ischemia patients, respectively. Thus, influx of serum proteins due to microvascular disturbances and hypoxia is proposed as a possible cause for vitreous alterations of IGF-I and of active TGF-β. These changes seem to occur late in the sequence of events leading to PDR and are not specific for diabetes, but they were also observed in other diseases characterized by retinal hypoxia.

Opiate alkaloids and opioid peptides have been shown to suppress plasma LH and FSH levels via a naloxone sensitive mechanism in several species including man. Three subtypes of opiate receptors have been characterized: mu, delta and kappa. The present study was designed to investigate their role in gonadotropin release. Three highly selective opioid ligands, DAGO, MRZ and DTE12 (a dimeric tetrapeptide enkephalin), were injected intraventricularly into chronically ovariectomized rats. Injection of the mu-agonist at doses of 1 and 10 nmol produced a significant suppression of LH secretion, while the delta- and kappa-agonists had no significant effect. Thus, the mu-receptor seems to be the primary opiate receptor involved in the regulation of LH secretion. None of the opiate agonists employed had an effect on FSH secretion.

Exercise exerts many health benefits by directly inducing molecular alterations in physically utilized skeletal muscle. Molecular adaptations of subcutaneous adipose tissue (SCAT) might also contribute to the prevention of metabolic diseases.To characterize the response of human SCAT based on changes in transcripts and mitochondrial respiration to acute and repeated bouts of exercise in comparison to skeletal muscle.Sedentary participants (27 ± 4 yrs) with overweight or obesity underwent 8-week supervised endurance exercise 3×1h/week at 80% VO2peak. Before, 60 min after the first and last exercise bout and 5 days post intervention, biopsies were taken for transcriptomic analyses and high-resolution respirometry (n = 14, 8 female/6 male).In SCAT, we found 37 acutely regulated transcripts (FC > 1.2, FDR < 10%) after the first exercise bout compared to 394, respectively, in skeletal muscle. Regulation of only 5 transcripts overlapped between tissues highlighting their differential response. Upstream and enrichment analyses revealed reduced transcripts of lipid uptake, storage and lipogenesis directly after exercise in SCAT and point to β-adrenergic regulation as potential major driver. The data also suggest an exercise-induced modulation of the circadian clock in SCAT. Neither term was associated with transcriptomic changes in skeletal muscle. No evidence for beigeing/browning was found in SCAT along with unchanged respiration.Adipose tissue responds completely distinct from adaptations of skeletal muscle to exercise. The acute and repeated reduction in transcripts of lipid storage and lipogenesis, interconnected with a modulated circadian rhythm, can counteract metabolic syndrome progression toward diabetes.

Results are presented of a two-pion interferometry (HBT) analysis in Pb+Au collisions at 40, 80, and 158 AGeV. A detailed study of the Bertsch-Pratt HBT radius parameters has been performed as function of the mean pair transverse momentum $k_t$ and in bins of the centrality of the collision. From these results we extract model dependent information about the space-time evolution of the reaction. An investigation of the effective volume of the pion emitting system provides an important tool to study the properties of thermal pion freeze-out.

Based on an evaluation of data on pion interferometry and on particle yields at midrapidity, we propose a universal condition for thermal freeze-out of pions in heavy-ion collisions. We show that freeze-out occurs when the mean free path of pions lambda(f) reaches a value of about 1 fm, which is much smaller than the spatial extent of the system at freeze-out. This critical mean free path is independent of the centrality of the collision and beam energy from the Alternating Gradient Synchrotron to the Relativistic Heavy Ion Collider.

Protein kinase C (PK-C) seems to be involved in the regulation of growth and differentiation of normal epithelial cells. Colonic adenomas and carcinomas show increased proliferation and decreased differentiation. We investigated the activity and subcellular distribution of PK-C in biopsies of normal, neoplastic, and malignant colonic epithelium to evaluate alterations in enzyme activity. In the control group (n = 7), the activity of PK-C was highest in the distal ileum (597 pmol/min/mg protein) and declined to the lowest amounts in rectal mucosa (225 pmol/min/mg protein). In patients with colonic adenomas (n = 16), total PK-C activity was significantly reduced as compared to adjacent mucosa (146 versus 336 pmol/min/mg protein, P less than 0.05) and to values determined in the control group (372 pmol/min/mg protein, P less than 0.01). The reduction of total PK-C activity in the adenoma group was even more evident in intraindividual comparison to paired adjacent mucosa (41.8% of adjacent mucosa, P less than 0.001). Specific activity of membrane-associated PK-C was equally decreased in colonic adenomas (36.3 pmol/min/mg protein) when compared to adjacent mucosa (102 pmol/min/mg protein, P less than 0.05) or to the control group (107 pmol/min/mg protein). In patients with colonic carcinomas (n = 10), the amount of total PK-C activity was also decreased (198 pmol/min/mg protein) when compared to adjacent mucosa or to the control group (P less than 0.05). In addition, the amount of membrane-associated PK-C activity (89.1 pmol/min/mg protein) was significantly reduced in carcinoma when compared to adjacent mucosa (P less than 0.05). The ratio of membrane-associated/total PK-C was not altered in adenomas, while in patients bearing carcinomas the relative fraction of membrane-associated PK-C activity was increased in samples from carcinomas and equally from adjacent colonic mucosa (45.0 and 44.6 versus 28.9%, P less than 0.05) when compared to controls. These results indicate that alterations within the protein kinase C pathway occur as early events in the adenoma-carcinoma sequence of intestinal mucosa, suggesting an important role of PK-C in epithelial differentiation and growth.

We describe the two RICH detectors of the CERES electron pair spectrometer at the CERN SPS which are used for electron identification and, in conjunction with a novel silicon drift detector, for tracking in pp, pA and AA collisions. The RICH detectors are operated at a high γth ⋍ 32 (CH4 at 1 atm.) and are thus rather insensitive to hadrons. The UV-detectors are multistep counters with a multiwire chamber as the last stage. They are operated at gains of 2–4 × 105 using a mixture of He + 6% C2H6 (or CH4) + TMAE. The two UV-detectors are equipped with 53 800 (48 400) square pads. The front end electronics consists of modules with 256 (121) channels, based on a 64-channel charge-sensitive preamplifier VLSI chip. The total readout time is 280 (1600) μs per event. Subsets of the pad data are used as input to a fast trigger processor selecting events with at least two separated electron rings. The trigger achieved an enrichment factor of ∼ 100 in proton-induced interactions, and a factor of ∼3 in 32SAu collisions. The RICH detectors perform very close to their design values. We observe clean Cherenkov rings with an average number of 11.2 (12.5) photons/ring. This is consistent with the calculated value N0 = 131 (75) cm−1 within the systematical error of about 10%. The spatial resolutions of 1.0 and 0.8 mrad (rms) for individual photons are dominated by chromatic aberration and in very good agreement with theoretical expectations.

We report preliminary results of the first measurement of low-mass electron pairs in 160 GeV/nucleon PbAu collisions at central rapidities in a wide multiplicity range. This work is the continuation of our systematic studies on pair production in p-Be, p-Au and SAu interactions. The motivation for this effort derives from a new source of lowmass dileptons recently observed in SAu and S-W collisions by CERES and HELIOS/3, respectively. The results obtained in the analysis of the PbAu data confirm our previous finding that pair production in the mass range 0.2 < mee < 1.5 GeV/c2 is enhanced over the contributions from hadron decays while no significant excess could be observed for mee ≲ 2mπ. A comparison of the results for different multiplicity bins favours a non-linear dependence of the e+e−-yield on the accompanying charged particle densities.

The epidermal growth factor (EGF) receptor and its various ligands (EGF, TGF-alpha, amphiregulin, heparin-binding (HB)-EGF, heregulin, betacellulin) seem to be involved in the growth regulation of intestinal mucosa and might be related to the development and progression of gastrointestinal tumors. However, few quantitative data investigating the impact of tumor-EGF receptor levels in gastrointestinal carcinomas on tumor stage and prognosis are available. Therefore, EGF receptors were quantitatively determined in colorectal carcinomas in comparison to adjacent normal mucosa by 125I[EGF]-binding studies. EGFR capacity was increased in advanced invasive colorectal carcinomas (T1/2 vs. T3/4 tumors, p<0.001) and advanced UICC stages (UICC I vs. UICC II/III, p<0.001). These findings were confirmed with quantitative 125[I]EGF autoradiography performed on frozen tissue slides and analyzed by laser densitometry (p=0.020). EGF receptor analysis with immunohistochemistry with EGFR antibodies directed against the extracellular domain of the receptor was not correlated with tumor invasion or prognosis. mRNA-expression of EGFR ligands was investigated using semiquantitative RT-PCR amplification using specific primers. RT-PCR transcripts of EGFR ligands (EGF, TGF-alpha, HB-EGF, and amphiregulin) were detected in both carcinomas and normal mucosa, indicating that autocrine growth stimulation of colorectal carcinomas is mediated by coexpression of EGF receptor ligands and upregulation of EGF receptors. Survival of colorectal cancer patients with increased tumor EGF receptor levels was significantly reduced in comparison to patients with low/unchanged tumor EGF receptor levels (mean survival+/-SD, 36.2+/-4.0 vs. 46.8+/-4.3 months; p=0.017). Further studies investigating EGF receptor levels in gastric cancer patients have shown that increased tumor EGF receptor levels were associated with poor prognosis in gastric cancer patients with tumors localized distal from the cardia. Several specific EGF receptor tyrosine kinase inhibitors have recently entered clinical phase I-III studies, with promising antitumor effects in several tumors, including gastrointestinal cancer. Therefore, patients with invasive gastric or colorectal carcinomas might benefit from therapies specifically blocking EGFR-mediated signal transduction.

A silicon drift detector of circular geometry giving unambiguously the radial and azimuthal coordinates of particle's interaction point for events with high multiplicity is part of the experimental set up of the NA45 experiment at CERN SPS. The paper reviews the characteristics of the detector and of its assembly among the other detectors of the experiment. The first experimental results showing the performance of the detector in term of resolution and its effectiveness in reconstructing the position of the event are reported.

Elliptic flow and two-particle azimuthal correlations of charged hadrons and high-p(T) pions (p(T)>1 GeV/c) have been measured close to midrapidity in 158A GeV/c Pb+Au collisions by the CERES experiment. Elliptic flow (v(2)) rises linearly with p(T) to a value of about 10% at 2 GeV/c. Beyond p(T) approximately 1.5 GeV/c, the slope decreases considerably, possibly indicating a saturation of v(2) at high p(T). Two-pion azimuthal anisotropies for p(T)>1.2 GeV/c exceed the elliptic flow values by about 60% in midcentral collisions. These nonflow contributions are attributed to nearside and back-to-back jetlike correlations, the latter exhibiting centrality dependent broadening.

The cytokine tumor necrosis factor alpha (TNF alpha) was proposed to mediate obesity related insulin resistance upon production in fat cells and to participate in tissue remodelling leading to vascular complications upon being released by macrophages. To assess its putative role in diabetes we determined plasma levels of TNF alpha in 105 adult humans. Male nondiabetic subjects had significantly lower TNF alpha levels than female controls (4.4 +/- 0.3, n = 17 vs. 6.6 +/- 1.0 pg/ml, n = 13; p = 0.049). Men with NIDDM had elevated TNF alpha (6.7 +/- 0.6 pg/ml, n = 34) compared to nondiabetic subjects (4.4 +/- 0.3 pg/ml, n = 17; p = 0.012). Such a difference was not apparent in women. Levels of TNF alpha were correlated with serum triglyceride levels in male controls (r2 = 0.64; p = 0.007) but not in NIDDM. Neither body mass index nor glycosylated hemoglobin correlated with TNF alpha in any of the groups. The presence of retinopathy (p = 0.046) but not of neuropathy or nephropathy or macroangiopathy was associated with significantly elevated plasma TNF alpha. We conclude that plasma levels of TNF alpha are sex-dependent and that increased TNF alpha occurs in male but not female NIDDM and may participate in the development of diabetic complications.

The design, calibration, and performance of the first radial drift Time Projection Chamber (TPC) are presented. The TPC was built and installed at the CERES/NA45 experiment at the CERN SPS in the late nineties, with the objective to improve the momentum resolution of the spectrometer. The upgraded experiment took data twice, in 1999 and in 2000. After a detailed study of residual distortions a spatial resolution of 340 um in the azimuthal and 640 um in the radial direction was achieved, corresponding to a momentum resolution of Dp/p = sqrt{(1% * p/GeV)^2 + (2%)^2}.

The control of ACTH secretion by opiates seems to involve stimulatory and inhibitory pathways, since opiate agonists and antagonists are capable of releasing ACTH in conscious rats. To elucidate the role of different opiate receptors in the control of ACTH release, rats were treated with receptor-selective opiate agonists and antagonists. The mu-opiate agonists, morphine and (D-Ala2,MePhe4,Gly5-ol)enkephalin, and the benzomorphan kappa-opiate agonists, MR 2034 and MRZ 2549, both stimulated ACTH release after central or peripheral injection. The effects of morphine, but not those of MR 2034, were blocked by a low dose of naloxone (50 ug/kg) and by the mu-receptor antagonist, beta-funaltrexamine. A 20 times higher dose of naloxone also blocked the effects of the kappa-agonist. Our data suggest that both mu- and kappa-opiate receptors are involved in the stimulation of ACTH release in rats.

The commercial library Optimization 2.1 for interactive multi-criteria optimization tasks has been released along with Dymola 2013.The library offers several numerical optimization algorithms for solving different kinds of optimization tasks.User defined Modelica functions or models provide the basis for an interactive optimization process where the user keeps overview of complex multi-criteria optimization tasks that can take discrete parameters, several model operating points or trajectories into account.Computational performance of optimization runs can be significantly increased by parallel numerical integrations of the Modelica model on multicore machines.

During the 1996 lead run time, CERES has accumulated 42 million events, corresponding to a factor of 5 more statistics than in 1995 and 2.5 million events of a special photon-run. We report on the results of the low-mass e+e−-pair analysis. Since the most critical item is the poor signal-to-background ratio we also discuss the understanding of this background, in absolute terms, with the help of a detailed Monte Carlo simulation. We show preliminary results of the photon analysis and summarize the results of the hadron analysis preliminarily reported on already at QM'97 [1].

The HELIOS experiment has measured inclusivep ⊥ spectra of negative particles in the rapidity region 1.0<y<1.9. The general shape of thep ⊥ spectra in p +W, O+W and S+W is similar, but cannot be described by a single exponential. Compared to p+p collisions, an excess is observed for low and highp ⊥. This effect increases with the projectile mass. Except for very lowE ⊥, the average transverse momentum <p ⊥> is found to be approximately constant up to the highest accessible values ofE ⊥.

The involvement of mu- and kappa-opiate receptors in the regulation of LH and prolactin secretion was investigated in long-term ovariectomized rats using selective opiate receptor agonists and antagonists. The mu-agonists morphine and [D-Ala2,MePhe4,Gly5-ol]-enkephalin (DAGO) suppressed LH levels in a dose-related manner. The benzomorphane (-)-5,9-dimethyl-2'-hydroxy-2-(tetrahydrofurfuryl)-6,7-benzomorphan tartrate (MR 2034; a designated kappa-agonist) also suppressed LH levels, whereas another benzomorphane kappa-agonist (-)-5,9-dimethyl-2'-hydroxy-2-(2-methoxy-propyl)-6,7-benzomorphan hydrobromide (MRZ 2549) had no effect on the levels of this hormone. Pretreatment with the highly selective mu-antagonist beta-funaltrexamine (beta-FNA), the fumarate methyl ester derivative of naltrexone, blocked the actions of both mu-agonists and MR 2034, indicating that opiate suppression of LH secretion is mediated by mu-receptors. This was further confirmed by in-vitro studies: the KCl-induced release of LHRH from perifused hypothalami obtained from ovariectomized rats was significantly reduced by DAGO but not by MRZ 2549. Prolactin secretion was stimulated in a dose-dependent manner by both mu- and kappa-agonists. The stimulation caused by morphine and DAGO was antagonized by beta-FNA, whereas that caused by the kappa-agonists MR 2034 and MZR 2549 was resistant to blockade by beta-FNA but not by naloxone (an antagonist which blocks all classes of opiate receptors when given in high doses). Thus prolactin secretion seems to be regulated by both mu- and kappa-opiate receptors, whereas the effects on LH secretion seem to involve mu-receptors only.

The 2000 W society, achievable through cuts in resource consumption and per capita CO2 emissions, is closely related to the goals of sustainable development. This study identifies the specific targets that need to be met both globally and by Switzerland to realize the vision. As a major energy consumer, the buildings sector will have to make a substantial contribution to meeting these targets. The report starts by examining the energy-saving potential of individual residential buildings through different combinations of building standard and building services system. Various building concepts already available today offer considerable potential and, as individual solutions, often achieve the targets of the 2000 W society. Yet, as the impact of such individual solutions on the building stock is dampened by a range of factors (e.g. long refurbishment cycles, low energy prices, scepticism of investors towards new technology), the effective gains fall far short of the theoretical potential. As the considered implementation scenarios and building stock projections show, the average buildings-sector targets required for the 2000 W society are nonetheless attainable. However, in order to tap the potential in the residential buildings sector, there is an urgent need for immediate action at various levels (e.g. through financial incentive systems, consumer information campaigns).

The Statistical Toolkit is a project for the development of open source software tools for statistical data analysis in experimental particle and nuclear physics. The second development cycle encompassed an extension of the software functionality and new tools to facilitate its usage in experimental environments. The new developments include additional goodness-of-fit tests, new implementations of existing tests to improve their statistical precision or computational performance, a new component to extend the usability of the toolkit with other data analysis systems, and new tools for an easier configuration and build of the system in the user's computing environment. The computational performance of all the algorithms implemented has been studied

Angiopoietin-like protein 8 (ANGPTL8)/betatrophin expression in visceral adipose tissue and associations with circulating fatty acid profile have not yet been investigated.Forty subjects were included in a cross-sectional study, 57 in a dietary weight reduction intervention. Circulating Angiopoietin-like protein 8/betatrophin was measured in all subjects. Liver and adipose tissue were sampled and plasma fatty acids and tissue Angiopoietin-like protein 8/betatrophin expression were evaluated in the cross-sectional study. In the intervention study oral glucose testing and liver magnetic resonance scanning at baseline and after 6 months were performed. Angiopoietin-like protein 8/betatrophin mRNA was increased in visceral compared to subcutaneous adipose tissue (p<0.001). Circulating ANGPTL8/betatrophin correlated with liver steatosis (r=0.42, p=0.047), triacylglycerols (r=0.34, p=0.046), saturated (r=0.43, p=0.022), monounsaturated (r=0.51, p=0.007), and polyunsaturated fatty acids (r=-0.53, p=0.004). In the intervention study, baseline Angiopoietin-like protein 8/betatrophin correlated with age (r=0.32, p=0.010) and triacylglycerols (r=0.30, p=0.02) and was increased with hepatic steatosis (p=0.033). Weight loss reduced liver fat by 45% and circulating Angiopoietin-like protein 8/betatrophin by 11% (288±17 vs. 258±17 pg/ml; p=0.015). Angiopoietin-like protein 8/betatrophin is related to liver steatosis, while visceral adipose tissue represents an additional site of expression in humans.

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with the metabolic syndrome and type 2 diabetes and independently contributes to long-term complications. Being often asymptomatic but reversible, it would require population-wide screening, but direct diagnostics are either too invasive (liver biopsy), costly (MRI) or depending on the examiner's expertise (ultrasonography). Hepatosteatosis is usually accommodated by features of the metabolic syndrome (e.g. obesity, disturbances in triglyceride and glucose metabolism), and signs of hepatocellular damage, all of which are reflected by biomarkers, which poorly predict NAFLD as single item, but provide a cheap diagnostic alternative when integrated into composite liver fat indices. Fatty liver index, NAFLD LFS, and hepatic steatosis index are common and accurate indices for NAFLD prediction, but show limited accuracy for liver fat quantification. Other indices are rarely used. Hepatic fibrosis scores are commonly used in clinical practice, but their mandatory reflection of fibrotic reorganization, hepatic injury or systemic sequelae reduces sensitivity for the diagnosis of simple steatosis. Diet-induced liver fat changes are poorly reflected by liver fat indices, depending on the intervention and its specific impact of weight loss on NAFLD. This limited validity in longitudinal settings stimulates research for new equations. Adipokines, hepatokines, markers of cellular integrity, genetic variants but also simple and inexpensive routine parameters might be potential components. Currently, liver fat indices lack precision for NAFLD prediction or monitoring in individual patients, but in large cohorts they may substitute nonexistent imaging data and serve as a compound biomarker of metabolic syndrome and its cardiometabolic sequelae.

A climate version of the nonhydrostatic fifth‐generation Penn State/NCAR Mesoscale Model has been used to downscale a global climate scenario to cloud‐resolving scales over complex terrain (the Alps). After first describing the model and methodology, we then present comparison results from the model‐predicted and ensemble‐averaged regional‐scale winter and summer season precipitation distribution with results from the global simulation and analyzed observed precipitation climatologies. Finally, results from the cloud‐resolving simulations are compared to the regional simulations. It is shown that the degree to which the terrain is resolved in the various runs significantly alters the simulation of the precipitation climatologies. This is caused not only by the complex interaction of the flow with the topography but also by the different treatment of the convective processes (resolved versus nonresolved) in the model. Even in winter, the model‐simulated seasonally averaged precipitation patterns change drastically with every increase in horizontal resolution. Furthermore, with a horizontal grid resolution of 1km, when seen on a local scale and over complex terrain, the model‐simulated precipitation patterns are not guaranteed to converge to one solution. This behavior is still more complicated in summer. Here it is shown that parameterized convection in the regional model simulation tends to be locked to the mountains, while in the cloud‐resolving simulations the convection moves with the upper level flow, producing precipitation maxima away from the mountain tops.

Spins and parities of states in 83Br and 85Br were determined from angular distributions of cross sections σ(θ) and analyzing powers iT11(θ) measured in the (d, 3He) reaction on 84Kr and 86Kr. Broad, unresolved structures between 3 MeV and 10 MeV excitation energy were attributed to the deeply bound, highly fragmented 1f72 shell. The lowest moments of the proton strength distributions observed in pickup and stripping experiments on a number of nuclei in the Zr region were determined and systematic properties of single particle energies and spreading widths were deduced.

Initiation of cell growth frequently involves activation of growth factor receptor-coupled tyrosine kinases and stimulation of the phosphoinositide second messenger system. The antitrypanosomal and antifiliarial drug suramin has been shown to exert antiproliferative activities by inhibition of growth factor receptor binding. We therefore investigated the effect of suramin on epidermal growth factor receptor-binding characteristics and, additionally, searched for effects on basal or cholinergically stimulated phospholipid metabolism in HT-29 cells. Suramin caused a dose-dependent and noncompetitive inhibition of 125I-epidermal growth factor binding (concentration producing 50% inhibition, 44.2 micrograms/ml) but did not alter muscarinic receptor binding. Suramin did not affect the basal 32P incorporation into phosphoinositides at concentrations of less than 200 micrograms/ml suramin. In contrast, the carbachol-stimulated enhancement of 32P incorporation into phosphatidic acid, phosphatidylinositol, and polyphosphoinositides was reduced by 48-95% in the presence of 100 micrograms/ml suramin. Thus, phosphoinositide and diacylglycerol kinases involved in basal and receptor-stimulated phosphoinositide metabolism may be localized in different subcellular compartments, which can be dissociated by the use of suramin. Direct measurements of phosphatidylinositol kinase and diacylglycerol kinase activities showed a potent inhibition when treated with suramin. Suramin did not affect the stimulation of phospholipase C by carbachol, determined by release of [3H]inositol phosphates in [3H]myoinositol-prelabeled cells. Our data indicate that suramin potently inhibits phosphoinositide resynthesis under stimulated conditions. Additionally, we confirm the inhibitory effects of suramin on epidermal growth factor receptor binding in a human intestinal cell line. The inhibitory effects of suramin on phospholipid metabolism may play a role in the antiproliferative actions of this drug.

Abstract. The present study investigates a statistical approach for the downscaling of climate simulations focusing on those meteorological parameters most commonly required as input for climate change impact models (temperature, precipitation, air humidity and wind speed), including the option to correct biases in the climate model simulations. The approach is evaluated by the utilization of a hydrometeorological model chain consisting of (i) the regional climate model MM5 (driven by reanalysis data at the boundaries of the model domain), (ii) the downscaling and model interface SCALMET, and (iii) the physically based hydrological model PROMET. The results of different hydrological model runs set up for the historical period 1971–2000 are compared to discharge recordings at the gauge of the Upper Danube Watershed (Central Europe) on a daily time basis. To avoid "in-sample" evaluation, a cross-validation approach is followed splitting the period in two halves of 15 yr. While one half is utilized to derive the downscaling functions based on spatially distributed observations (e.g. 1971–1985), the other is used for the application of the downscaling functions within the hydrometeorological model chain (e.g. 1986–2000). By alternately using both parts for the generation and the application of the downscaling functions, discharge simulations are generated for the whole period 1971–2000. The comparison of discharge simulations and observations reveals that the presented approaches allow for a more accurate simulation of discharge in the catchment of the Upper Danube Watershed and the considered gauge at the outlet in Achleiten. The correction for subgrid-scale variability is shown to reduce biases in simulated discharge compared to the utilization of bilinear interpolation. Further enhancements in model performance could be achieved by a correction of biases in the RCM data within the downscaling process. These findings apply to the cross-validation experiment as well as to an "in-sample" application, where the whole period 1971–2000 is used for the generation and the application of the downscaling functions. Although the presented downscaling approach strongly improves the performance of the hydrological model, deviations from the observed discharge conditions persist that are not found when driving the hydrological model with spatially distributed meteorological observations.

We report on the production of low-mass electron pairs and muon pairs in p-Be collisions at 450 GeV/c at the CERN SPS. For both electron and muon pairs the low-mass spectrum can be explained satisfactorily by lepton pairs from hadronic decays, and there is no need to invoke any "unconventional" source. The normalisation of the major hadronic sources is set by the data. The upper limit, at 90% confidence level, on any new source of lepton pairs is ∼20% of the hadronic decay contribution for muons, and ∼40% for electrons.

CERES is an experiment dedicated to measure e+ e−-pairs in nucleus-nucleus collisions at the CERN SPS. Following the experiences gained with proton and sulfur beams the CERES spectrometer was upgraded to cope with the much larger charged particle densities produced in PbPb collisions. Major parts of the upgrade were completed in time for a 10 days test with a lead beam in November 1994. The results clearly demonstrate the feasibility of the experiment in the environment of central PbPb collisions.

A search for non-statistical fluctuations was performed in 200 GeV per nucleon oxygen and sulphur ion-emulsion interactions selected by a high transverse energy trigger. No clear signal of dynamical correlations or of unusual fluctuations was found.

An evaluation of precipitation fields for four selected months simulated by the regional climate model At-moMM5 and provided by the satellite retrieval method AtmoSat is presented. As reference, observations at 5 km resolution on a daily and monthly basis are used. We applied conventional verification tools (root mean square error, grid-point based categorical error scores, etc.) as well as the new error score SAL, which separately considers aspects of the structure, amplitude and location of the precipitation field in a predefined area. We also discussed the advantages and disadvantages of each of the scores. The aim of our evaluation was to unfold the strengths and weaknesses of AtmoMM5 and AtmoSat to calculate daily and monthly high resolution precipitation. As a result we found that the catchment averaged monthly mean precipitation is simulated with an acceptable accuracy by both methods. The spatial pattern of the monthly precipitation (typically with a precipitation maximum in the alpine foreland) can only be reproduced by AtmoMM5. Regarding the daily precipitation, our evaluation revealed that both methods still need improvement. The deviations to the observations increase with decreasing precipitation amount resulting in large uncertainties in case of very dry conditions. Overall, we can conclude that AtmoMM5 is better suited to simulate precipitation at 5 km resolution on a daily basis than AtmoSat.

The presence of different types of opiate binding sites was investigated with the use of a computerized, weighted, nonlinear least-squares regression program. The experimental data were obtained from four groups. Each of three labeled opiate ligands was displaced using each of the same unlabeled ligands. The resulting nine different ligand combinations of each group were evaluated by use of a curve-fitting program. The four groups consisted of the kappa ligand ethylketocyclazocine, the sigma ligand SKF 10047, and the oripavine derivatives etorphine and diprenorphine, each in conjunction with the delta opiate receptor ligand (D-Ala2,D-Leu5)-enkephalin and the mu opiate receptor ligand dihydromorphine. The binding model which best fitted each of the four groups suggested the existence of three different binding sites in the rat brain homogenate. Two of these sites conform to the previously described mu and delta sites. A third site (R3) displayed high affinity for ethylketocyclazocine, SKF 10047, etorphine, and diprenorphine but very low affinity for dihydromorphine and [D-Ala2,D-Leu5]enkephalin. Naloxone, cyclazocine, and dynorphin-(1--13) had high affinity for R3. Behavioral data support the interpretation that the R3 site may represent a kappa site at which SKF 10047 acts antagonistically.

We present results on transverse momentum correlations of charged particle pairs produced in PbAu collisions at 158A GeV/c at the Super Proton Synchrotron. The transverse momentum correlations have been studied as a function of collision centrality, angular separation of the particle pairs, transverse momentum and charge sign. We demonstrate that the results are in agreement with previous findings in scale-independent analyses at the same beam energy. Employing the two-particle momentum correlator 〈Δpt,i,Δpt,j〉 and the cumulative pt variable x(pt), we identify, using the scale-dependent approach presented in this paper, different sources contributing to the measured correlations, such as quantum and Coulomb correlations, elliptic flow and mini-jet fragmentation.

Purpose of review Life expectancy of people with severe mental illness is considerably shortened and their risk for cardiovascular and metabolic disorders is increased. They spend more time in solitary and less time in structured activities than the general population. Engagement in healthy patterns of activity, including active, meaningful participation in the community can, therefore, be critical to recovery from severe mental illness. Occupational therapy is a profession that focuses on time use, activity patterns and occupational engagement, and the links to health and well-being. In this study, we review research evidence regarding approaches to occupational engagement, including behavioural activation, time use, and activity promotion. We also will review studies that specifically evaluate the impact of occupational therapy interventions. Recent findings There is a growing body of evidence regarding the value of interventions addressing occupational engagement of individuals with severe mental illness, including a range of activation strategies and approaches. There is a need, however, for documentation of theoretically informed approaches that are supported by fidelity measures to ensure standardization. Summary Larger-scale studies are needed, including consistent outcome measures to document engagement and changes in activity patterns as well as health-related outcomes. High-quality randomized clinical trials are important to establish effectiveness. As occupational therapy interventions are complex and embedded within a range of multidisciplinary approaches, new models of pragmatic trials within the naturalistic context of psychiatric rehabilitation are also needed.

This practice guideline is aimed at all professional groups caring for people with type 2 diabetes mellitus (T2Dm). In addition to the multifaceted aspects of nutrition in diabetes, there is a particular call for individualization of therapy, counseling, empowerment, and diabetes self-management [1] [2] [3]. Therefore, the Nutrition Committee of the DDG has set the goal to compile practice guidelines on nutrition as target group-specific as possible with the highest available evidence. In doing so, it is considered necessary to treatment forms separately presentation since the therapeutic significance of nutrition differs significantly in each case and must be seen against the background of different drug therapy components.

Some individuals develop type 2 diabetes mellitus (T2DM) despite significant metabolic improvements through lifestyle intervention. We tested the hypotheses that insulin growth factor 1 (IGF1) and its binding proteins 1 and 2 predict the onset of T2DM in prediabetes patients and determine the capacity for metabolic regeneration.We measured fasting serum IGF1, insulin growth factor-binding protein 1 (IGFBP1) and IGFBP2 in three randomized controlled lifestyle intervention trials, covering at least 1 year of intervention period and 1 year of additional follow-up.Within a sample of 414 high-risk prediabetes patients (58% women; 28-80 years), we analyzed fasting serum concentrations of IGF1, IGFBP1 and IGFBP2 in relation to diabetes incidence and metabolic parameters over 2 years. Three hundred and forty-five subjects finished the first year of intervention.The interventions significantly improved body weight (BMI: -3.24%, P < 0.001), liver fat (-36.8%, P < 0.001), insulin sensitivity (IS) (homeostatic model assessment-insulin resistance: -6.3%, P < 0.001) and insulin secretion (disposition index: +35%, P < 0.001) in the cohort. Fourteen percent developed T2DM within 2 years. Mean IGFBP1 levels at baseline were lower in prediabetes compared to a healthy population. Also, prediabetes patients with obesity and nonalcoholic fatty liver disease had lower IGFBP1. Those with impaired glucose tolerance had higher IGFBP1 compared to those with only impaired fasting glucose. Baseline IGF1 was lower (122.5 vs 146.6 µg/L) and IGFBP1 was higher (3.32 vs 2.09 µg/L) in subjects who developed T2DM (n = 57), resulting in a significant prediction of diabetes incidence (hazard ratio (HR) IGF1: 0.991 µg/L, P = 0.003; HR IGFBP1: 1.061 µg/L, P = 0.002). This translates into a 20% and 9% difference in T2DM incidence for IGF1 and IGFBP1, respectively. Despite reduced weight, visceral fat and hepatic fat in response to 1 year of lifestyle intervention, those who developed T2DM had not improved insulin sensitivity, glucose tolerance or IGFBP1.Lower IGF1 and higher IGFBP1 in prediabetes predicted the incidence of T2DM, indicating an impairment of beta-cell function, which explains the unresponsiveness to lifestyle intervention.

Short-term trials indicate improvement of intrahepatic lipids (IHLs) and metabolism by dietary protein or unsaturated fatty acids (UFAs) beyond weight loss. We aimed to assess the effect of a dietary intervention high in protein and UFAs on IHLs and metabolic outcome after 12 mo, as long-term effects of such a combined intervention are unknown. Within a 36-mo randomized controlled trial, eligible subjects (aged 50 to 80 y, ≥1 risk factor for unhealthy aging) were randomly assigned to either intervention group (IG) with high intake of mono-/poly-UFAs [15–20 percent of total energy (%E)/10%–15%E, respectively], plant protein (15%–25%E), and fiber (≥30 g/d), or control group [CG, usual care, dietary recommendations of the German Nutrition Society (fat 30%E/carbohydrates 55%E/protein 15%E)]. Stratification criteria were sex, known cardiovascular disease, heart failure, arterial hypertension, type 2 diabetes, and cognitive or physical impairment. Nutritional counseling and supplementation of foods mirroring the intended dietary pattern were performed in the IG. Diet-induced effects on IHLs, analyzed by magnetic resonance spectroscopy, as well as on lipid and glucose metabolism were predefined secondary endpoints. IHL content was analyzed in 346 subjects without significant alcohol consumption at baseline and in 258 subjects after 12 mo. Adjusted for weight loss, sex, and age, we observed a comparable decline of IHLs in IG and CG (−33.3%; 95% CI: −49.3, −12.3%; n = 128 compared with -21.8%; 95% CI: −39.7, 1.5%; n = 130; P = 0.179), an effect that became significant by comparing adherent IG subjects to adherent CG subjects (−42.1%; 95% CI: −58.1, −20.1%; n = 88 compared with -22.2%; 95% CI: −40.7, 2.0%; n = 121; P = 0.013). Compared with the CG, decline of LDL cholesterol (LDL-C) and total cholesterol (TC) was stronger in the IG (for LDL-C P = 0.019, for TC P = 0.010). Both groups decreased in triglycerides and insulin resistance (P for difference between groups P = 0.799 and P = 0.124, respectively). Diets enriched with protein and UFAs have beneficial long-term effects on liver fat and lipid metabolism in adherent older subjects. This study was registered at the German Clinical Trials Register, https://www.drks.de/drks_web/setLocale_EN.do, DRKS00010049. Am J Clin Nutr 20XX;xx:xx–xx.

Hydrogen-based direct reduction is a promising technology for CO2 lean steelmaking. The electric arc furnace is the most relevant aggregate for processing direct reduced iron (DRI). As DRI is usually added into the arc, the behavior in this area is of great interest. A laboratory-scale hydrogen plasma smelting reduction (HPSR) reactor was used to analyze that under inert conditions. Four cases were compared: carbon-free and carbon-containing DRI from DR-grade pellets as well as fines from a fluidized bed reactor were melted batch-wise. A slag layer’s influence was investigated using DRI from the BF-grade pellets and the continuous addition of slag-forming oxides. While carbon-free materials show a porous structure with gangue entrapments, the carburized DRI forms a dense regulus with the oxides collected on top. The test with slag-forming oxides demonstrates the mixing effect of the arc’s electromagnetic forces. The cross-section shows a steel melt framed by a slag layer. These experiments match the past work in that carburized DRI is preferable, and material feed to the hotspot is critical for the EAF operation.

Notice Of Update The DDG clinical practice guidelines are updated regularly during the second half of the calendar year. Please ensure that you read and cite the respective current version.

We assessed the effect of a dietary pattern rich in unsaturated fatty acids (UFA), protein and fibers, without emphasizing energy restriction, on visceral adipose tissue (VAT) and cardiometabolic risk profile. Within the 36-months randomized controlled NutriAct trial, we randomly assigned 502 participants (50–80 years) to an intervention or control group (IG, CG). The dietary pattern of the IG includes high intake of mono-/polyunsaturated fatty acids (MUFA/PUFA 15–20% E/10–15% E), predominantly plant protein (15–25% E) and fiber (≥30 g/day). The CG followed usual care with intake of 30% E fat, 55% E carbohydrates and 15% E protein. Here, we analyzed VAT in a subgroup of 300 participants via MRI at baseline and after 12 months, and performed further metabolic phenotyping. A small but comparable BMI reduction was seen in both groups (mean difference IG vs. CG: −0.216 kg/m2 [−0.477; 0.045], partial η2 = 0.009, p = 0.105). VAT significantly decreased in the IG but remained unchanged in the CG (mean difference IG vs. CG: −0.162 L [−0.314; −0.011], partial η2 = 0.015, p = 0.036). Change in VAT was mediated by an increase in PUFA intake (ß = −0.03, p = 0.005) and induced a decline in LDL cholesterol (ß = 0.11, p = 0.038). The NutriAct dietary pattern, particularly due to high PUFA content, effectively reduces VAT and cardiometabolic risk markers, independent of body weight loss.

Do multiple ascending doses (MAD) of LY3537021 (LY), a selective, long-acting GIP receptor agonist, result in weight loss (WL) effects versus placebo?

Wie wir kürzlich zeigen konnten, wird eine Remission von Prädiabetes durch verbesserte Insulinsensitivität (IS) vermittelt und ist gekennzeichnet durch eine Reduktion des viszeralen Fettgewebes (VAT). Remission reduziert das Risiko für Typ 2 Diabetes (T2D) deutlich. Aufgrund dieser Daten prüfen wir die Hypothese, dass Personen spezifischer Hoch-Risiko-Gruppen der Tübinger Prädiabetes-Cluster eine verminderte Remissionsrate nach Lebensstilintervention (LI) zeigen.

Wir konnten kürzlich zeigen, dass im Rahmen einer Lebensstilintervention (LI) eine Prädiabetes-Remission durch Gewichtsverlust aufgrund gesteigerter Insulinsensitivität vermittelt wird und dass dadurch das Risiko, einen Typ 2 Diabetes (T2D) zu entwickeln, sinkt. Ob eine Prädiabetes-Remission auch bei Personen, die im Verlauf der LI kein Gewicht verlieren oder sogar zunehmen, erreicht werden kann und ob die zugrundeliegenden Mechanismen sich von denen der gewichtsverlust-abhängigen Remission unterscheiden, ist nicht bekannt.

The CMSWEB cluster is pivotal to the activities of the Compact Muon Solenoid (CMS) experiment, as it hosts critical services required for the operational needs of the CMS experiment. The security of these services and the corresponding data is crucial to CMS. Any malicious attack can compromise the availability of our services. Therefore, it is important to construct a robust security infrastructure. In this work, we discuss new security features introduced to the CMSWEB Kubernetes (“k8s”) cluster. The new features include the implementation of network policies, deployment of Open Policy Agent (OPA), enforcement of OPA policies, and the integration of Vault. The network policies act as an inside-the-cluster firewall to limit the network communication between the pods to the minimum necessary, and its dynamic nature allows us to work with microservices. The OPA validates the objects against some custom-defined policies during create, update, and delete operations to further enhance security. Without recompiling or changing the configuration of the Kubernetes API server, it can apply customized policies on Kubernetes objects and their audit functionality enabling us to detect pre-existing conflicts and issues. Although Kubernetes incorporates the concepts of secrets, they are only base64 encoded and are not dynamically configured. This is where Vault comes into play: Vault dynamically secures, stores, and tightly controls access to sensitive data. This way, the secret information is encrypted, secured, and centralized, making it more scalable and easier to manage. Thus, the implementation of these three security features corroborate the enhanced security and reliability of the CMSWEB Kubernetes infrastructure.

The Ca2+/calmodulin dependent protein kinase II (CaM kinase II) is thought to play an important part in glucose-stimulated insulin secretion. To determine which of the known subtypes (alpha, beta, gamma, delta) occur in insulin-secreting cells, we amplified all types of CaM kinase II by RT-PCR and found the beta3-, gamma-, delta2- and delta6-subtypes in RINm5F insulinoma cells. None of the other 8 delta-subtypes was present. Antibodies generated against the bacterially expressed association domain of the delta2-subtype recognized the recombinant gamma and delta-subtypes. In INS-1 and RINm5F cells, as well as freshly isolated rat islets, only a 55-kDa protein corresponding in size to the delta2-subtype expressed in NIH3T3 fibroblasts was detected. The delta2-subtype therefore appears to represent the predominant subtype of CaM kinase II present in insulin secreting cells. The enzyme was primarily associated with cytoskeletal structures, and very little was present in the soluble compartment or detergent soluble fraction in INS-1- or RINm5F-cells. An analysis of its subcellular distribution was performed by sucrose and Nycodenz density gradient fractionation of INS-1 cells and detection of CaM kinase II delta by immune blots. The enzyme codistributed with insulin used as a marker for secretory granules but not with the lighter synaptic-like microvesicles detected with an antibody against synaptophysin, plasma membranes (syntaxin 1), lysosomes (arylsulfatase), or mitochondria (cytochrome c oxidase). CaM kinase II delta2 thus is identified as the subtype associated with insulin secretory granules and is likely to be involved in insulin secretion.

We discuss the latest theoretical results on direct photon and dilepton production from relativistic heavy-ion collisions. While the dilepton spectra at low invariant mass show in-medium effects like collisional broadening of the vector meson spectral functions, the dilepton yield at high invariant masses (above 1.1 GeV) is dominated by QGP contributions for central heavy-ion collisions at relativistic energies. The present status of the photon v2 “puzzle” – a large elliptic flow v2 of the direct photons experimentally observed at RHIC and LHC energies – is also addressed. The role of hadronic and partonic sources for the photon spectra and v2 is considered as well as the possibility to subtract the QGP signal from the experimental observables.

Transverse-energy distributions have been measured for the collisions of the 32S nucleus with Al, Ag, W, Pt, Pb, and U target nuclei, at an incident energy of 200 GeV per nucleon. The shapes of these distribution reflect the geometry of the collisions, including the deformation effects. For central collisions, the transverse-energy production in the region −0.1<ηlab<2.9 increases approximately as A0.5, where A is the atomic mass number of the target. This increase is accompanied by a relative depletion in the forward region ηlab > 2.9. These results are compared with those obtained under similar conditions with incident 16O nuclei. A comparison is also made with the predictions of a Monte Carlo generator based on the dual parton model. Finally, we give estimates of the energy density reached and its dependence on the atomic mass number of the projectile.

Using hybridization techniques and Northern blots we have identified a approximately 6.5 kb glucocorticoid receptor mRNA species in rat pituitary intermediate lobe. Glucocorticoid receptor mRNA concentrations, which are barely detectable or undetectable in normal animals, were greatly increased following ovariectomy. This ovariectomy-induced increase in glucocorticoid receptor mRNA content of the intermediate lobe, which was confirmed by in situ hybridization experiments, could be reversed by 17 beta-estradiol administration.

Exhaust cowls are used in conjunction with hybrid ventilation systems to efficiently convert wind energy into negative pressure and thus minimize the electrical energy required by the extract fan. Yet the fact that cowl performance is largely dictated by operating conditions imposes particularly stringent demands on modelling. This paper demonstrates, by way of a concrete example, the need for and potential benefits of a new methodological approach to the modelling of cowls. The study focuses on a specific modelling strategy, applied within a building simulation program, for a cowl used in a hybrid ventilation system. The method is progressively simplified to produce four variants, which chiefly vary according to their level of detail and, hence, the associated modelling effort. Wind pressure coefficients at facade, above roof and in the cowl are needed for all model variants. Some of the investigated variants rely on CFD computations of airflow around the building to determine these values. This study uses the example of a single-family house (SFH) to identify those criteria requiring particular attention in the performance of CFD numerical flow analyses. All four variants are examined on the basis of this example to determine which simplifications to the model are appropriate and permissible without unduly compromising the accuracy of the results.

Glucagon (GCGN) plays a key role in glucose and amino acid (AA) metabolism by increasing hepatic glucose output. AA strongly stimulate GCGN secretion which regulates hepatic AA degradation by ureagenesis. Although increased fasting GCGN levels cause hyperglycemia GCGN has beneficial actions by stimulating hepatic lipolysis and improving insulin sensitivity through alanine induced activation of AMPK. Indeed, stimulating prandial GCGN secretion by isocaloric high protein diets (HPDs) strongly reduces intrahepatic lipids (IHLs) and improves glucose metabolism in type 2 diabetes mellitus (T2DM). Therefore, the role of GCGN and circulating AAs in metabolic improvements in 31 patients with T2DM consuming HPD was investigated. Six weeks HPD strongly coordinated GCGN and AA levels with IHL and insulin sensitivity as shown by significant correlations compared to baseline. Reduction of IHL during the intervention by 42% significantly improved insulin sensitivity [homeostatic model assessment for insulin resistance (HOMA-IR) or hyperinsulinemic euglycemic clamps] but not fasting GCGN or AA levels. By contrast, GCGN secretion in mixed meal tolerance tests (MMTTs) decreased depending on IHL reduction together with a selective reduction of GCGN-regulated alanine levels indicating greater GCGN sensitivity. HPD aligned glucose metabolism with GCGN actions. Meal stimulated, but not fasting GCGN, was related to reduced liver fat and improved insulin sensitivity. This supports the concept of GCGN-induced hepatic lipolysis and alanine- and ureagenesis-induced activation of AMPK by HPD.

The objective of this work was to investigate whether impaired insulin secretion can be restored by lifestyle intervention in specific subphenotypes of prediabetes. We assigned 1,045 participants from the Prediabetes Lifestyle Intervention Study (PLIS) to six recently established prediabetes clusters. Insulin secretion was assessed by a C-peptide-based index derived from oral glucose tolerance tests and modeled from three time points during a 1-year intervention. We also analyzed the change of glycemia, insulin sensitivity, and liver fat. All prediabetes high-risk clusters (cluster 3, 5, and 6) had improved glycemic traits during the lifestyle intervention, whereas insulin secretion only increased in clusters 3 and 5 (P < 0.001); however, high liver fat in cluster 5 was associated with a failure to improve insulin secretion (Pinteraction < 0.001). Thus, interventions to reduce liver fat have the potential to improve insulin secretion in a defined subgroup of prediabetes.

Relatively selective mu-, delta- and kappa-opiate agonists were microinjected into anterior hypothalamic and septal brain regions of the unanesthetized rat in order to investigate the potential role of specific opiate receptors in central cardiovascular regulation. Low doses (0.2-3 nmol) of both [D-Ala2,MePhe4,Gly-(ol)5] enkephalin (DAGO, mu-agonist) and [D-Ala2,D-Leu5]enkephalin (DADL, delta-agonist) caused dose-dependent increases in blood pressure and heart rate which were naloxone reversible. Higher doses (7.5-30 nmol) of DAGO and DADL produced pressor responses but had little effect on heart rate. The kappa-agonist MR 2034 had no effect on cardiovascular parameters at these doses. DAGO but not MR 2034 also depressed respiration at the higher doses resulting in hypoxia, hypercapnia and acidosis while DADL only slightly depressed respiration. DAGO was approximately 10-fold more potent than DADL in eliciting cardiovascular and respiratory responses. These findings implicate mu-receptors in mediating the cardiovascular and respiratory effects of opiates at anterior hypothalamic sites.

Rats were treated for 4 weeks with a constant infusion of 2 mg/kg/h of the opiate antagonist naloxone. This treatment increased μ-, σ- and ξ-binding sites by 60–180% in several brain regions, suggesting effective blockade of the 3 types of opiate sites. The significance of changes in opiate binding sites for opiate receptor mediated physiological responses were examined using cardiovascular and respiratory responses to morphine (assessed after elimination of naloxone) as physiological parameters. Chronically naloxone-treated rats showed no alteration in respiratory responses to morphine, whereas there was a marked supersensitivity to depressor and bradycardic effects and a loss of pressor and tachycardic effects of morphine. These data are the first indication that cardiovascular effects of opiates vary with changes in central opiate receptor levels. Our observations, moreover, show that there are complex relationships between receptor number and receptor-mediated effects of opiates.

A statistical method is presented to downscale precipitation from a mesoscale atmospheric model simulation. The algorithm consists of two steps. First, local subscale variability is estimated based on a high resolution observed climatology. Second, there is a bias correction, which constrains the downscaled model climatology to be equal to the observed climatology on the coarse grid. Combining both steps results in a local scaling factor for each day of the climatological year. The method is applied to the upper Danube catchment which encompasses part of the European Alps and which is characterized by highly complex orography. The subgrid-scale variability described by the first part of the algorithm partly reflects the underlying orography, especially the narrow alpine valleys. The bias correction leads to a redistribution of precipitation on the catchment scale and accounts for the model deficiency producing too much precipitation in the inner alpine regions and too little at the edges of the Alps. An evaluation with regard to the simulated and observed daily precipitation indicating the significant potential of the method is presented.

Abstract This study examines small‐scale precipitation patterns in a north‐Alpine region, and their dependence on the freezing level and on the crest‐level (700 hPa) wind direction and speed. On the one hand, measurements from a uniquely dense operational rain‐gauge network are analyzed for a period of 15 years (1991‐‐2005). Information on the ambient atmospheric fields was extracted from climate‐mode MM5 simulations driven with ECMWF (re‐analysis data. On the other hand, high‐resolution semi‐idealized MM5 simulations have been conducted, combining realistic topography with idealized atmospheric fields. The atmospheric flow parameters have been chosen to be representative of those used to classify the observational data, focusing on atmospheric conditions conducive to stratiform, orographically enhanced precipitation in the region under consideration. The results of the data analysis indicate a pronounced tendency for local precipitation maxima in the lee of individual mountain ridges, whereas the variability between stations in the centre of wider valleys and stations on the windward foot of individual ridges is comparatively small. This points towards a strong contribution of local precipitation enhancement due to the seeder‐‐feeder mechanism, combined with downstream advection of the precipitating hydrometeors by the ambient winds. The data analysis also reveals that strong winds and high temperatures tend to shift the precipitation field towards the interior of the Alps, whereas low temperatures and weak winds favour precipitation maxima near the northern edge of the Alps. The semi‐idealized simulations are consistent with these findings, but their quantitative agreement with the observed precipitation patterns depends on the ambient flow conditions. The closest agreement is found for atmospheric conditions conducive to strong orographic lifting, for which our present idealized flow fields were designed. Lower skill is obtained for conditions not dominated by orographic lifting, which implies that future work should include a generalization of the idealized flow fields. Nevertheless, precipitation patterns generated with semi‐idealized simulations seem to be very promising to support the spatial interpolation of point measurements (such as are needed for precipitation climatologies), which currently is usually based on statistical methods rather than physically motivated structures. Copyright © 2008 Royal Meteorological Society

Abstract. Downstream models are often used in order to study regional impacts of climate and climate change on the land surface. For this purpose, they are usually driven offline (i.e., 1-way) with results from regional climate models (RCMs). However, the offline approach does not allow for feedbacks between these models. Thereby, the land surface of the downstream model is usually completely different to the land surface which is used within the RCM. Thus, this study aims at investigating the inconsistencies that arise when driving a downstream model offline instead of interactively coupled with the RCM, due to different feedbacks from the use of different land surface models (LSM). Therefore, two physically based LSMs which developed from different disciplinary backgrounds are compared in our study: while the NOAH-LSM was developed for the use within RCMs, PROMET was originally developed to answer hydrological questions on the local to regional scale. Thereby, the models use different physical formulations on different spatial scales and different parameterizations of the same land surface processes that lead to inconsistencies when driving PROMET offline with RCM output. Processes that contribute to these inconsistencies are, as described in this study, net radiation due to land use related albedo and emissivity differences, the redistribution of this net radiation over sensible and latent heat, for example, due to different assumptions about land use impermeability or soil hydraulic reasons caused by different plant and soil parameterizations. As a result, simulated evapotranspiration, e.g., shows considerable differences of max. 280 mm yr−1. For a full interactive coupling (i.e., 2-way) between PROMET and the atmospheric part of the RCM, PROMET returns the land surface energy fluxes to the RCM and, thus, provides the lower boundary conditions for the RCM subsequently. Accordingly, the RCM responses to the replacement of the LSM with overall increased annual mean near surface air temperature (+1 K) and less annual precipitation (−56 mm) with different spatial and temporal behaviour. Finally, feedbacks can set up positive and negative effects on simulated evapotranspiration, resulting in a decrease of evapotranspiration South of the Alps a moderate increase North of the Alps. The inconsistencies are quantified and account for up to 30% from July to Semptember when focused to an area around Milan, Italy.

Since the European Union defined ambitious CO2 emission targets, low-carbon-emission alternatives to the widespread integrated blast furnace (BF)-basic oxygen furnace (BOF) steelmaking strategy-are demanded. Direct reduction (DR) with natural gas as the reducing agent, already an industrially applied technology, is such an alternative. Consequently, the melting behavior of its intermediate product, i.e., direct reduced iron (DRI), in either an electric arc furnace (EAF) or a submerged arc furnace (SAF), is of great interest. Based on the conditions in these aggregates, a test series to experimentally simulate the first few seconds after charging DRI was defined. DRI samples with different carbon contents and hot briquetted iron (HBI) were immersed in high- and low-carbon melts as well as high- and low-iron oxide slags. The reacted samples were quenched in liquid nitrogen. The specimens were qualitatively evaluated by investigating their surfaces and cross sections. The dissolution of carbon-free DRI progressed relatively slowly and was driven by heat transfer. However, carbon, present either in the DRI sample or in the melt, not only accelerated the dissolution process, but also reacted with residual iron oxide in the pellet or the slag.

Six different ligands of the epidermal-growth-factor receptor (EGFR) have been identified in the past. In some cervical squamous-cell carcinomas, an increased amount of proteins binding to the EGFR has been reported. In order to identify the mRNA of EGFR ligands (EGFRL), which might be over-expressed in cervical and endometrial cancers, we performed semi-quantitative reverse-transcription/polymerase chain reactions (RT-PCR) for all 6 EGFRL in RNA extracts of normal and malignant tissue samples of the human uterus. PCR products from RNA extracts of 83 patients were quantitated relative to the housekeeping gene and internal standard pyruvate dehydrogenase by analyzing the PCR kinetics of product synthesis. In extracts of normal cervix, the level of mRNA expression of the EGFRL was significantly higher than in endometrium. No significant difference was detected between normal cervix and cervical carcinomas. However, both in cervical and in endometrial cancers, mRNA expression was non-parametrically distributed and in some cervical cancers overexpression of transforming growth factor alpha (TGF-α), amphiregulin or EGF was observed. In endometrial cancers, mRNA levels of all EGFRL were higher than in normal endometrium. This increase was significant (p < 0.005) for TGF-α and amphiregulin. Thus, TGF-α mRNA is over-expressed in approximately 10% of cervical cancers and in the majority of endometrial cancers. Since TGF-α anti-sense therapy might represent a future strategy in such cancers, we also determined the absolute level of TGF-α mRNA expression by quantitative PCR using a cloned standard. Int. J. Cancer 72:581–586, 1997.© 1997 Wiley-Liss, Inc.

The CERES/NA45 collaboration measured, at the CERN SPS, low-mass electron pair production in PbAu collisions at 158 A GeV/c incident momentum. In this paper we present an analysis of the data taken during the SPS Pb-beam period in the fall of 1995. The results confirm previous findings of CERES showing that the pair production in the mass range 0.2 <mee < 1.5 GeV/c2, when scaled to the ion case with the event multiplicity, is enhanced over the expected yield from the known hadronic sources in pp collisions. A comparison of the results for different multiplicity bins indicates that the excess increases faster than linearly with charged-particle multiplicity. We also present the transverse-momentum distributions of the observed pairs.

The EGF receptor/ligand system seems to be involved in the regulation of gastric mucosa proliferation and progression of gastric carcinomas.EGF receptor levels were quantitatively determined in 47 gastric carcinomas by 125J [EGF] radioreceptor assays in membrane preparations of tumor samples or corresponding adjacent mucosa. Specific receptor binding was determined by the analysis of displacement curves by non-linear least-square regression analysis using an estimated model of 'goodness of fit'.Increased EGF receptor binding was observed in gastric carcinomas (mean +/- SEM: 11.87 +/- 1.9 fmol/mg protein) in comparison to adjacent normal gastric mucosa ( 5.28 +/- 1.0 fmol/mg protein, p = 0.003). Elevated EGF receptor levels were especially found in more invasive T3/4 carcinomas, tumors with positive lymph nodes, advanced UICC III carcinomas, undifferentiated tumors, carcinomas of the diffuse-type according to Lauren's classification and gastric carcinomas localized distal from the cardia. In histopathologically normal appearing gastric mucosa, EGF-receptor levels were significantly decreased relative to corresponding tumor samples from advanced UICC stages (UICC I vs UICC I/II: p = 0.008) or tumors with low levels of differentiation (G2 vs G3: p = 0.028). Overall survival was significantly reduced in patients with advanced gastric carcinomas according to UICC classification (UICC III vs UICC I/II: 18.8 vs 45.5 months, p = 0.016). A subgroup analysis of gastric carcinomas localized distal from the cardia indicated, that increased EGF-receptor levels were an independent indicator of poor prognosis as determined by univariate (p = 0.020) and multivariate analysis (p = 0.042).Gastric carcinomas with increased EGF receptors might be a possible target for anticancer strategies blocking the EGF receptor/ligand pathway.

The transverse energy distributions have been measured for interactions of 32S nuclei with Al, Ag, W, Pt, Pb, and U targets, at an incident energy of 200 GeV per nucleon in the pseudorapidity region −0.1 < νlab < 5.5. These distributions are compared with those for 16OW interactions in the same pseudorapidity region and with earlier measurements performed with 16O and 32S projectiles in the region −0.1 < νlab < 2.9. These comparisons provide both a better understanding of the dynamics involved and improved estimates of stopping power and energy density.

How can Python users be empowered with the robust simulation, compilation and scripting abilities of a nonproprietary object-oriented, equation based modeling language such as Modelica?The immediate objective of this work is to develop an application programming interface for the OpenModelica modeling and simulation environment that would bridge the gap between the two agile programming languages Python and Modelica.The Python interface to OpenModelica -OMPython, is both a tool and a functional library that allows Python users to realize the full capabilities of OpenModelica's scripting and simulation environment requiring minimal setup actions.OMPython is designed to combine both the simulation and model building processes.Thus domain experts (people writing the models) and computational engineers (people writing the solver code) can work on one unified tool that is industrially viable for optimization of Modelica models, while offering a flexible platform for algorithm development and research.

We have for the first time identified e+e−-pairs produced by strongly varying electromagnetic fields in distant SPt collisions at 200 GeV/u projectile energy at the CERN-SPS. The differential cross section for the mass range 10 MeV/c2 ≤ mee ≤ 100 MeV/c2 and the polar angle range 141 mrad ≤ θe ≤ 260 mrad agrees well with a lowest-order perturbation QED-calculation.

We have measured the inclusivep T spectra of soft photons produced at central and backward rapidities in 450 GeV/cp-Be collisions down to 1 MeV/c in transverse momentum. In the region 1<p T <20 MeV/c an excess of photons over those expected from hadronic decays is observed. This excess is comparable, within systematic errors, with estimates of direct photons produced via hadronic bremsstrahlung. An upper limit is derived on the presence of additional sources of direct photons at small transverse momentum.

Diffractive dissociation of nuclei (Be, Al, W) in collisions with 450 GeV/c protons,pA→pX, has been measured with the HELIOS spectrometer at the CERN Super Proton synchrotron. The dependence of the single-diffraction cross-section on the nuclear massA can be parametrized as σSD mb×A 0.35±0.02, showing the peripheral nature of the process. The differential cross-section dσSD=(3.8±0.3)mb ×A 0.35±0.02, is exponential with the slope parameter, increasing from 6.2±0.4 (GeV/c)−2 for beryllium to 7.9±0.5 (GeV/c)−2 for tungsten. The slope parameter also increases with increasing massM X of the diffractively produced state. The rapidity, multiplicity, and transverse-momentum distributions of the particles of the diffractively produced stateX show a longitudinal phase-space population and are remarkably insensitive to the nuclear mass. This, together with theA 1/3 dependence of σSD, suggests that the dominant process of nuclear diffractive excitation is the dissociation of single nucleons.

A 42-yr-old woman with long-standing ulcerative colitis of the descending colon, sigmoid, and rectum presented with bloody diarrhea, tenesmus, and high fever. Endoscopic findings were compatible with an acute attack of ulcerative colitis, which proved to be resistant to systemic corticosteroid treatment. In the presence of an acute abdomen with ascites and double-contoured colonic wall, hemicolectomy was performed. Postoperatively, high temperature, hyponatremia, and elevated liver enzyme levels persisted. Pleural effusions developed. Antibodies to Legionella pneumophila serogroup 3 were detected in the serum. Erythromycin therapy induced rapid improvement. In a massive submucosal edema of the affected colon, L. pneumophila of the same serogroup was demonstrated by direct immunofluorescence staining.

Sustainable mobility, based on battery-powered electrical propulsion concepts, has been rediscovered in 2008 through emerging technology developments and enviromental requirements. Since 2009 a charging infrastructure for transportation on the basis of electrified powertrains has been developed all over Europe. Access to the charging stations is monitored by intelligent Triple-A-Systems (AAA - Authentication, Authorisation and Accounting) for reasons of security, customer loyalty and accounting. Similar to roaming in mobile communications, it should be possible for pioneers of e-mobility to have access to public charging stations of different operators. This article describes an efficient and future-oriented architecture of Clearinghouse systems that will provide interoperability and information exchange for e-mobility applications.

A new simulation and analysis environment in Python is introduced.The environment provides a graphical user interface for simulating different model types (currently Functional Mockup Units and Modelica Models), plotting result variables and applying simulation result analysis tools like Fast Fourier Transform.Additionally advanced tools for linear system analysis are provided that can be applied to the automatically linearized models.The modular concept of the software enables easy development of further plugins for both simulation and analysis.

In this paper we propose a method how to automatically utilize continuous-time Modelica models directly in nonlinear state estimators.The approach is based on an extended FMI 2.0 Co-Simulation Interface [1] that interacts with the state estimation algorithms implemented in a Modelica library [2].Besides a short introduction to Kalman Filter based state estimation, we give details on a generic interface to cooperate with FMUs in Modelica, an implementation of nonlinear state estimation based on this interface, and the Dymola prototype used for the evaluation.Finally we show first results in a tire load estimation application [3] for DLR's robotic electric research platform ROMO [4].

Software performance testing is an essential quality assurance mechanism that can identify optimization opportunities. Automating this process requires strong tool support, especially in the case of Continuous Integration (CI) where tests need to run completely automatically and it is desirable to provide developers with actionable feedback. A lack of existing tools means that performance testing is normally left out of the scope of CI. In this paper, we propose a toolchain - PerfCI - to pave the way for developers to easily set up and carry out automated performance testing under CI. Our toolchain is based on allowing users to (1) specify performance testing tasks, (2) analyze unit tests on a variety of python projects ranging from scripts to full-blown flask-based web services, by extending a performance analysis framework (VyPR) and (3) evaluate performance data to get feedback on the code. We demonstrate the feasibility of our toolchain by using it on a web service running at the Compact Muon Solenoid (CMS) experiment at the world's largest particle physics laboratory --- CERN.

Abstract This paper summarizes the various storage options that we implemented for the CMSWEB cluster in Kubernetes infrastructure. All CMSWEB services require storage for logs, while some services also require storage for data. We also provide a feasibility analysis of various storage options and describe the pros/cons of each technique from the perspective of the CMSWEB cluster and its users. In the end, we also propose recommendations according to the service needs. The first option is the CephFS which can be mounted multiple times across various clusters and VMs and works very well with k8s. We use it both for data and the logs. The second option is the Cinder volume. It is the block storage that runs the filesystem on top of it. It can only be attached to one instance at a time. We use this option only for the data. The third option is S3 storage. It is object storage that offers a scalable storage service that can be used by applications compatible with the Amazon S3 protocol. It is used for the logs. For S3, we explored two mechanisms. For the first scenario, we consider fluentd that runs as a sidecar container in the service pods and sends logs to S3 bucket. For the second scenario, we considered filebeat that runs as a sidecar container in the service pod and scaps those logs to fluentd which runs as a daemonset in each node and sends those logs to S3 in the end. The fourth option is EOS. We configured EOS inside the pods of the CMSWEB services. The fifth option that we explored is to use dedicated VMs that have Ceph volume attached to them. In EOS and VM, the logs from the service pods are sent to EOS/VM using the rsync approach. The last option is to send service logs to Elasticsearch. It has been implemented using fluentd that runs as a daemonset in each node. In parallel to the sending logs to S3 fluentd also sends those logs to the Elasticsearch infrastructure at CERN.

Background Glucagon (GCG) plays an important role in the early development of diabetes by causing a feed-forward cycle of hyperinsulinemia and insulin resistance. The opposite view emphasizes that intra-islet alpha-beta-cell crosstalk is essential for intact insulin secretion and GCG determines hepatic fat oxidation, thus supporting intact metabolism. We investigated the role of GCG in diabetes remission within our “FAIR” study - Fasting-Associated Immune-metabolic Remission of Diabetes.

In the context of type 2 diabetes (T2DM), fasting and postprandial hyperglucagonemia have long been linked to the disease&amp;#039;s development and progression. However, recent studies have brought to light the positive impact of glucagon-agonists on lipid metabolism and energy homeostasis. This review delves into the intricate relationship and underlying mechanisms between glucagon and nutrient composition, which may hold promise in devising novel therapeutic approaches for T2DM management.

Hadronic spectra from interactions of Pb on Au at 158 AGeV/c have been measured by the CERES experiment at the CERN SPS. We report on preliminary results on transverse mass spectra of identified pions and negative hadrons as well as spectra of the positive charge excess obtained by subtracting the negative particle distribution from that of positive tracks. We have also performed a study of the event azimuthal anisotropies which give evidence for directed and elliptic flow in non-central collisions.

Inclusive photonp ⊥ spectra were measured with 200 GeV/u proton,16O and32S beams on W and Pt targets, using a conversion method. The measurement of charged pions in the same apparatus allows a comparison of the γ data with the expected γ's from hadronic decays π0, η, η', ω). In all data sets, no deviation from the expected shape is observed in the range of 0.1<p ⊥<1.5 GeV/c. The number of photons normalized to pions agrees within the statistical (4%–11%) and systematical (9%) errors with the number of photons expected from hadronic decays in the integrated ranges ranges ofp ⊥>0.1 GeV/c andp ⊥>0.6 GeV/c.

Rotating heat exchangers (RHEs) transfer contaminants from exhaust to supply air in several ways: with entrained air, through possible leakage around the wheel at the separation wall, and by condensation–evaporation or adsorption–desorption. Leakage from exhaust to supply was measured in several units using the tracer gas dilution technique, and found negligible if not absent in most cases. Leakage can be strongly reduced through a proper installation of the wheel, good maintenance of the gasket, proper installation of a purging sector, and maintaining a positive pressure differential from supply to exhaust duct at wheel level. Pollutant transfer was measured by flash-evaporating a cocktail of 12 chemical compounds in the extract duct, and measuring their concentrations at four points within the air handling unit, upwind and downwind, the heat exchanger in both supply and exhaust flows. The cocktail included diverse alcohols, aldehydes, and cyclic and aromatic hydrocarbons, as well as an ether, an alkane, and a haloalkane. This contribution discusses various transfer phenomena, presents the procedures used to quantify volatile organic compounds (VOCs) transfer and the results of detailed measurements in three units. The transfer rate strongly varies among chemical compounds. In a given chemical compound class, the transfer rate strongly increases with the boiling point. This supports the hypothesis that the main transfer phenomenon is adsorption–desorption.