hTERT mRNA dendritic cell vaccination: complete response in a pancreatic cancer patient associated with response against several hTERT epitopes

Immunotherapy targeting the hTERT subunit of telomerase has been shown to induce robust immune responses in cancer patients after vaccination with single hTERT peptides. Vaccination with dendritic cells (DCs) transfected with hTERT mRNA has the potential to induce strong immune responses to multiple hTERT epitopes and is therefore an attractive approach to more potent immunotherapy. Blood samples from such patients provide an opportunity for identification of new, in vivo processed T-cell epitopes that may be clinically relevant. A 62-year-old female patient underwent radical surgery for a pancreatic adenocarcinoma. After relapse, she obtained stable disease on gemcitabine treatment. Due to severe neutropenia, the chemotherapy was terminated. The patient has subsequently been treated with autologous DCs loaded with hTERT mRNA for 3 years. Immunomonitoring was performed at regular intervals following start of vaccination and clinical outcome measured by CT and PET/CT evaluation. The patient developed an immune response against several hTERT-derived Th and CTL epitopes. She presently shows no evidence of active disease based on PET/CT scans. No serious adverse events were experienced and the patient continues to receive regular booster injections. We here provide evidence for the induction of hTERT-specific immune responses following vaccination of a pancreas cancer patient with DCs loaded with hTERT mRNA. These responses are associated with complete remission. A thorough analysis of this patient immune response has provided a unique opportunity to identify novel epitopes, associated with clinical effects. These will be included in future hTERT vaccines.     

A stability analysis of the power-law steady state of marine size spectra

This paper investigates the stability of the power-law steady state often observed in marine ecosystems. Three dynamical systems are considered, describing the abundance of organisms as a function of body mass and time: a “jump-growth” equation, a first order approximation which is the widely used McKendrick–von Foerster equation, and a second order approximation which is the McKendrick–von Foerster equation with a diffusion term. All of these yield a power-law steady state. We derive, for the first time, the eigenvalue spectrum for the linearised evolution operator, under certain constraints on the parameters. This provides new knowledge of the stability properties of the power-law steady state. It is shown analytically that the steady state of the McKendrick–von Foerster equation without the diffusion term is always unstable. Furthermore, numerical plots show that eigenvalue spectra of the McKendrick–von Foerster equation with diffusion give a good approximation to those of the jump-growth equation. The steady state is more likely to be stable with a low preferred predator:prey mass ratio, a large diet breadth and a high feeding efficiency. The effects of demographic stochasticity are also investigated and it is concluded that these are likely to be small in real systems.     

Life cycle assessment of construction materials: the influence of assumptions in end-of-life modelling

Purpose

The nature of end-of-life (EoL) processes is highly uncertain for constructions built today. This uncertainty is often neglected in life cycle assessments (LCAs) of construction materials. This paper tests how EoL assumptions influence LCA comparisons of two alternative roof construction elements: glue-laminated wooden beams and steel frames. The assumptions tested include the type of technology and the use of attributional or consequential modelling approaches.

Methods

The study covers impact categories often considered in the construction industry: total and non-renewable primary energy demand, water depletion, global warming, eutrophication and photo-chemical oxidant creation. The following elements of the EoL processes are tested: energy source used in demolition, fuel type used for transportation to the disposal site, means of disposal and method for handling allocation problems of the EoL modelling. Two assumptions regarding technology development are tested: no development from today’s technologies and that today’s low-impact technologies have become representative for the average future technologies. For allocating environmental impacts of the waste handling to by-products (heat or recycled material), an attributional cut-off approach is compared with a consequential substitution approach. A scenario excluding all EoL processes is also considered.

Results and discussion

In all comparable scenarios, glulam beams have clear environmental benefits compared to steel frames, except for in a scenario in which steel frames are recycled and today’s average steel production is substituted, in which impacts are similar. The choice of methodological approach (attributional, consequential or fully disregarding EoL processes) does not seem to influence the relative performance of the compared construction elements. In absolute terms, four factors are shown to be critical for the results: whether EoL phases are considered at all, whether recycling or incineration is assumed in the disposal of glulam beams, whether a consequential or attributional approach is used in modelling the disposal processes and whether today’s average technology or a low-impact technology is assumed for the substituted technology.

Conclusions

The results suggest that EoL assumptions can be highly important for LCA comparisons of construction materials, particularly in absolute terms. Therefore, we recommend that EoL uncertainties are taken into consideration in any LCA of long-lived products. For the studied product type, LCA practitioners should particularly consider EoL assumptions regarding the means of disposal, the expected technology development of disposal processes and any substituted technology and the choice between attributional and consequential approaches.     

Effects of various squalene epoxides on coenzyme Q and cholesterol synthesis

2,3-Oxidosqualene is an intermediate in cholesterol biosynthesis and 2,3:22,23-dioxidosqualene act as the substrate for an alternative pathway that produces 24(S),25-epoxycholesterol which effects cholesterol homeostasis. In light of our previous findings concerning the biological effects of certain epoxidated all-trans-polyisoprenes, the effects of squalene carrying epoxy moieties on the second and third isoprene residues were investigated here. In cultures of HepG2 cells both monoepoxides of squalene and one of their hydrolytic products inhibited cholesterol synthesis and stimulated the synthesis of coenzyme Q (CoQ). Upon prolonged treatment the cholesterol content of these cells and its labeling with [³H]mevalonate were reduced, while the amount and labeling of CoQ increased. Injection of the squalene monoepoxides into mice once daily for 6 days elevated the level of CoQ in their blood, but did not change the cholesterol level. The same effects were observed upon treatment of apoE-deficient mice and diabetic GK-rats. This treatment increased the hepatic level of CoQ10 in mice, but the amount of CoQ9, which is the major form, was unaffected. The presence of the active compounds in the blood was supported by the finding that cholesterol synthesis in the white blood cells was inhibited. Since the ratio of CoQ9/CoQ10 varies depending on the experimental conditions, the cells were titrated with substrate and inhibitors, leading to the conclusion that the intracellular isopentenyl-PP pool is a regulator of this ratio. Our present findings indicate that oxidosqualenes may be useful for stimulating both the synthesis and level of CoQ both in vitro and in vivo.     

Hrr25 kinase promotes selective autophagy by phosphorylating the cargo receptor Atg19

Autophagy is the major pathway for the delivery of cytoplasmic material to the vacuole or lysosome. Selective autophagy is mediated by cargo receptors, which link the cargo to the scaffold protein Atg11 and to Atg8 family proteins on the forming autophagosomal membrane. We show that the essential kinase Hrr25 activates the cargo receptor Atg19 by phosphorylation, which is required to link cargo to the Atg11 scaffold, allowing selective autophagy to proceed. We also find that the Atg34 cargo receptor is regulated in a similar manner, suggesting a conserved mechanism.     

Structural and Electronic Snapshots during the Transition from a Cu(II) to Cu(I) Metal Center of a Lytic Polysaccharide Monooxygenase by X-ray Photoreduction

Lytic polysaccharide monooxygenases (LPMOs) are a recently discovered class of enzymes that employ a copper-mediated, oxidative mechanism to cleave glycosidic bonds. The LPMO catalytic mechanism likely requires that molecular oxygen first binds to Cu(I), but the oxidation state in many reported LPMO structures is ambiguous, and the changes in the LPMO active site required to accommodate both oxidation states of copper have not been fully elucidated. Here, a diffraction data collection strategy minimizing the deposited x-ray dose was used to solve the crystal structure of a chitin-specific LPMO from Enterococcus faecalis (EfaCBM33A) in the Cu(II)-bound form. Subsequently, the crystalline protein was photoreduced in the x-ray beam, which revealed structural changes associated with the conversion from the initial Cu(II)-oxidized form with two coordinated water molecules, which adopts a trigonal bipyramidal geometry, to a reduced Cu(I) form in a T-shaped geometry with no coordinated water molecules. A comprehensive survey of Cu(II) and Cu(I) structures in the Cambridge Structural Database unambiguously shows that the geometries observed in the least and most reduced structures reflect binding of Cu(II) and Cu(I), respectively. Quantum mechanical calculations of the oxidized and reduced active sites reveal little change in the electronic structure of the active site measured by the active site partial charges. Together with a previous theoretical investigation of a fungal LPMO, this suggests significant functional plasticity in LPMO active sites. Overall, this study provides molecular snapshots along the reduction process to activate the LPMO catalytic machinery and provides a general method for solving LPMO structures in both copper oxidation states.     

Die Hieracien der Umgebung von Seckau in Ober-Steiermark

Ohne Zusammenfassung     

Purification of the cytochalasin B binding component of the human erythrocyte monosaccharide transport system

The cytochalasin B binding component of the human erythrocyte monosaccharide transport system has been purified. The preparation appears to contain one major protein with an apparent polypeptide chain molecular weight of 55 000 and about 0.4 binding sites per chain. Cytochalasin B binds to the reconstituted preparation with a dissociation constant of 1.3·10^?7 M, a value which is similar to that reported for the transport system in the intact erythrocyte.     

Die Hausgottheiten der Frauen und das Geschlechtstabu bei den nordeurasischen Völkern

The notion that the individual and society articulate only tenuously, if not with tension, may be social scientific folklore. Human aptitudes involving creativity, independent thought, and agency generally, appear to be shaped and sometimes dictated by the socioculture. Social scientists have begun to unpack the issue of agency in order to better understand the relations among and between individuals and society. By exploring an empirical case involving a congregation of Svenska Missionsförbundet, one can establish that while the form of religious practice is individualistic, its content is strikingly communalistic. These practitioners, and other Swedes at large, often perceive a contradiction between the agendas of individual and of community, which conflict bears critical scrutiny.