Scientific Highlights
from the Research Department "Biology and Chemistry" (BIO)

The low-energy β− and electron emitter 161Tb as an alternative to 177Lu for targeted radionuclide therapy

Research Department Biology and Chemistry (BIO), Radionuclicde Development Group, Head Konstantin Zhernosekov. The low-energy β− emitter 161Tb is very similar to 177Lu with respect to half-life, beta energy and chemical properties. However, 161Tb also emits a significant amount of conversion and Auger electrons. Greater therapeutic effect can therefore be expected in comparison to 177Lu. It also emits low-energy photons that are useful for gamma camera imaging. The 160Gd(n,γ)161Gd→161Tb production route was used to produce 161Tb by neutron irradiation of massive 160Gd targets (up to 40 mg) in nuclear reactors. A semiautomated procedure based on cation exchange chromatography was developed and applied to isolate no carrier added (n.c.a.) 161Tb from the bulk of the 160Gd target and from its stable decay product 161Dy. 161Tb was used for radiolabeling DOTA-Tyr3-octreotate; the radiolabeling profile was compared to the commercially available n.c.a. 177Lu. A 161Tb Derenzo phantom was imaged using a small-animal single-photon emission computed tomography camera. Up to 15 GBq of 161Tb was produced by long-term irradiation of Gd targets. Using a cation exchange resin, we obtained 80%–90% of the available 161Tb with high specific activity, radionuclide and chemical purity and in quantities sufficient for therapeutic applications. The 161Tb obtained was of the quality required to prepare 161Tb–DOTA-Tyr3-octreotate. We were able to produce 161Tb in n.c.a. form by irradiating highly enriched 160Gd targets; it can be obtained in the quantity and quality required for the preparation of 161Tb-labeled therapeutic agents.

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Gas uptake and chemical aging of semisolid organic aerosol particles

Research Department Biology and Chemistry (BIO), Surface Chemistry Group, Head Markus Ammann. Organic substances can adopt an amorphous solid or semisolid state, influencing the rate of heterogeneous reactions and multiphase processes in atmospheric aerosols. Here we demonstrate how molecular diffusion in the condensed phase affects the gas uptake and chemical transformation of semisolid organic particles. Flow tube experiments show that the ozone uptake and oxidative aging of amorphous protein is kinetically limited by bulk diffusion. The reactive gas uptake exhibits a pronounced increase with relative humidity, which can be explained by a decrease of viscosity and increase of diffusivity due to hygroscopic water uptake transforming the amorphous organic matrix from a glassy to a semisolid state (moisture-induced phase transition). The reaction rate depends on the condensed phase diffusion coefficients of both the oxidant and the organic reactant molecules, which can be described by a kinetic multilayer flux model but not by the traditional resistor model approach of multiphase chemistry. The chemical lifetime of reactive compounds in atmospheric particles can increase from seconds to days as the rate of diffusion in semisolid phases can decrease by multiple orders of magnitude in response to low temperature or low relative humidity. The findings demonstrate that the occurrence and properties of amorphous semisolid phases challenge traditional views and require advanced formalisms for the description of organic particle formation and transformation in atmospheric models of aerosol effects on air quality, public health, and climate.

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The structural basis of agonist-induced activation in constitutively active rhodopsin

Research Department Biology and Chemistry (BIO), Membrane Proteins Structural Biology Group. G-protein-coupled receptors (GPCRs) comprise the largest family of membrane proteins in the human genome and mediate cellular responses to an extensive array of hormones, neurotransmitters and sensory stimuli. Although some crystal structures have been determined for GPCRs, most are for modified forms, showing little basal activity, and are bound to inverse agonists or antagonists. Consequently, these structures correspond to receptors in their inactive states. The visual pigment rhodopsin is the only GPCR for which structures exist that are thought to be in the active state. However, these structures are for the apoprotein, or opsin, form that does not contain the agonist all-trans retinal. Here we present a crystal structure at a resolution of 3 Å for the constitutively active rhodopsin mutant Glu 113 Gln, in complex with a peptide derived from the carboxy terminus of the α-subunit of the G protein transducin. The protein is in an active conformation that retains retinal in the binding pocket after photoactivation. Comparison with the structure of ground-state rhodopsin suggests how translocation of the retinal β-ionone ring leads to a rotation of transmembrane helix 6, which is the critical conformational change on activation. A key feature of this conformational change is a reorganization of water-mediated hydrogen-bond networks between the retinal-binding pocket and three of the most conserved GPCR sequence motifs. We thus show how an agonist ligand can activate its GPCR.

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The role of long-lived reactive oxygen intermediates in the reaction of ozone with aerosol particles

Research Department Biology and Chemistry (BIO), Surface Chemistry Group, Head Markus Ammann. The heterogeneous reactions of ozone with aerosol particles are of central importance to air quality. They are studied extensively, but the molecular mechanisms and kinetics remain unresolved. Based on new experimental data and calculations, we show that long-lived reactive oxygen intermediates (ROIs) are formed. The chemical lifetime of these intermediates exceeds 100 seconds, which is much longer than the surface residence time of molecular ozone (~ ns). The ROIs explain and resolve apparent discrepancies between earlier quantum mechanical calculations and kinetic experiments. They play a key role in the chemical transformation and adverse health effects of toxic and allergenic air-particulate matter, such as soot, polycyclic aromatic hydrocarbons and proteins. ROIs may also be involved in the decomposition of ozone on mineral dust and in the formation and growth of secondary organic aerosols. Moreover, ROIs may contribute to the coupling of atmospheric and biospheric multiphase processes.

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Recent increase in black carbon concentrations
from a Mt. Everest ice core spanning 1860–2000 AD

Research Department Biology and Chemistry (BIO), Analytical Chemistry Group, Head Margit Schwikowski. A Mt. Everest ice core spanning 1860–2000 AD and analyzed at high resolution for black carbon (BC) using a Single Particle Soot Photometer demonstrates strong seasonality, with peak concentrations during the winter‐spring, and low concentrations during the summer monsoon season. BC concentrations from 1975–2000 relative to 1860–1975 have increased approximately threefold, indicating that BC from anthropogenic sources is being transported to high elevation regions of the Himalaya. The timing of the increase in BC is consistent with BC emission inventory data from South Asia and the Middle East, however since 1990 the ice core BC record does not indicate continually increasing BC concentrations. The Everest BC and dust records provide information about absorbing impurities that can contribute to glacier melt by reducing the albedo of snow and ice. There is no increasing trend in dust concentrations since 1860, and estimated surface radiative forcing due to BC in snow exceeds that of dust in snow. This suggests that a reduction in BC emissions may be an effective means to reduce the effect of absorbing impurities on snow albedo and melt, which affects Himalayan glaciers and the availability of water resources in major Asian rivers.

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Site-Specific and Stoichiometric Modification of Antibodies by Bacterial Transglutaminase

Research Department Biology and Chemistry (BIO), Center for Radiopharmaceutical Science. Bacterial transglutaminase enables the site-specific modification of Gln side chains of tumor-targeting antibodies with various probes containing lysine or lysine surrogates. The method yields completely homogeneous immunoconjugates with a defined stoichiometry. In comparative in vivo studies with xenografted mice the pharmacological profiles for enzymatically conjugated antibodies were better than those of chemically modified analogues.

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A new proxy for regional temperature reconstruction?
Ammonium concentration in ice cores:

Analytical Chemistry Group, Head Margit Schwikowski. We present a reconstruction of tropical South American temperature anomalies over the last 1600 years. It is based on a highly resolved and carefully dated ammonium record from an ice core that was drilled in 1999 on Nevado Illimani in the eastern Bolivian Andes. The reconstruction reveals that Medieval Warm Period– and Little Ice Age–type episodes are distinguishable in tropical South America, a region for which until now only very limited temperature proxy data have been available. For the time period from about 1050 to 1300 AD relatively warm conditions occurred that are followed by cooler conditions from the 15th to the 18th century, when temperatures dropped by up to 0.6°C below the 1961–1990 average. The last decades of the past millennium are characterized again by warm temperatures that seem to be unprecedented in the context of the last 1600 years.

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The nature of nitrate at the ice surface

Surface Chemistry Research Group, Head Markus Ammann. Trace contaminants such as strong acids have been suggested to affect the thickness of the quasi-liquid layer at the ice/air interface, which is at the heart of heterogeneous chemical reactions between snowpacks or cirrus clouds and the surrounding air. We used X-ray photoelectron spectroscopy (XPS) and electron yield near edge X-ray absorption fine structure (NEXAFS) spectroscopy at the Advanced Light Source (ALS) to probe the ice surface in the presence of HNO₃ at 230 K. We studied the nature of the adsorbed species at the ice/vapor interfaces as well as the effect of HNO₃ on the hydrogen bonding environment at the ice surface. The NEXAFS spectrum of ice with adsorbed HNO₃ can be represented as linear combination of the clean ice and nitrate solution spectrum, thus indicating that in the presence of HNO₃ the ice surface consists of a mixture of clean ice and nitrate ions that are coordinated as in a concentrated solution at the same temperature but higher HNO₃ pressures.

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