Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants ported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of “feeding receptors” at the interface between neuroendocrine and mental diseases.

Potential PET Ligands for Imaging of Cerebral VPAC and PAC Receptors: Are Non-Peptide Small Molecules Superior to Peptide Compounds?

Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) have been known for decades to mediate neuroendocrine and vasodilative actions via G-protein-coupled receptors of Class B. These are targets of imaging probes for positron emission tomography (PET) or single photon emission tomography (SPECT) in tumor diagnostics and tumor grading. However, they play only a subordinate role in the development of tracers for brain imaging. Difficulties in development of non-peptide ligands typical for cerebral receptors of PACAP and VIP are shared by all members of Class B receptor family. Essential landmarks have been confirmed for understanding of structural details of Class B receptor molecular signalling during the last five years. High relevance in the explanation of problems in ligand development for these receptors is admitted to the large N-terminal?ectodomain markedly different from Class A receptor binding sites and poorly suitable as orthosteric binding sites for the most small-molecule compounds. The present study is focused on the recently available receptor ligands for PAC1, VPAC1 and VPAC2 receptors as well as potential small-molecule lead structures suitable for use in PET or SPECT. Recently, biaryl, cyanothiophene and pentanamide structures with affinities in nM-range have been proposed as non-peptide ligands at VPAC1 and VPAC2 receptors. However, most of these ligands have been classified as non-competitive related to the orthosteric binding site of endogenous peptide ligands of VPAC receptors. For PAC1 receptors have been identified hydrazide compounds for which an inhibitory and potentially competitive mechanism of receptor binding has been postulated based on molecular docking studies.

Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?

Neuropeptide receptors of the brain and spinal cord are parts of the pain circuits targeted by analgesic drugs. Some of these receptors have been found in the central nervous system as well as in intracranial vascular structures and achieved revival of attention because of their role in acute and chronic pain syndromes. A number of them are of high clinical relevance for e.g. migraine. Others participate in symptoms of rare diseases like amyotrophic lateral sclerosis. Here we will focus on five of the neuropeptide receptors and their non-peptide ligands potentially or already successfully used as PET probes. Opioid receptors and neurotensin receptors are known to mediate analgesic actions. Bradykinin and calcitonin gene-related peptide (CGRP) receptors are known to be involved in the regulation of vascular tone and inflammatory responses, and neurokinin receptors play a role in the occurrence of pain perception in a rather indirect manner. Most experiences as PET tracers have been gathered with opioid receptor ligands and neurokinin receptor ligands. The most innovative fields revealed by the studies summarized in this report are the ligands of κ opioid receptors and CGRP receptors for which a first PET tracer was presented recently.

Holocene climate change in the Central Tibetan Plateau inferred by lacustrine sediment geochemical records

Multi-proxies of lacustrine sediments, such as total carbon (TC), total organic carbon (TOC), total inorganic carbon (TIC), total nitrogen (TN), total sulfur (TS), hydrogen index (HI), oxygen index (OI) and stable carbon isotopic composition of organic matter (δ^(13)C_(org)), were analyzed using a 7.3 m core from Zige Tangco. The source of the organic matter in the sediment was mainly from autochthonous phyto-plankton, therefore the significances of proxies can be interpreted as that high TOC, TOC/TS, HI and δ^(13)C_(org) values, low TC, TIC values corresponded to warm and wet climatic condition, and vice versa. The process of climatic development in the Zige Tangco region was hence recovered. During the early and Mid-Holocene, the climate was warm and wet and intensive cold events occurred during the periods of 8600 to 8400 cal a BP and 7400 to 7000 cal a BP. In the second half of Holocene, the climate became cold and dry gradually. The palaeoclimatic process during Holocene in Zige Tangco region matched well with that in Co Ngoin region which is ca 40 km to the south-east. Therefore this palaeoclimatic process represents the Holocene climatic feature in the Central Tibetan Plateau which has the same pattern in the Northern Tibetan Plateau, but the time and duration of some climatic events might be different. We can conclude that in Holocene solar insolation controlled the climatic pattern on the central Tibetan Plateau.

青藏高原中部全新世气候变化的湖泊沉积地球化学记录

通过青藏高原中部兹格塘错湖泊沉积物总碳（TC）、总有机碳（TOC）、总氮（TN）、总硫（TS）、氢指数（HI）、氧指数（OI）和有机质的碳同位素（δ^13Corg）等多项指标的综合分析,在判断沉积物中有机质来源的基础上,根据各指标的变化特征阐明了各自的气候指示意义,建立了兹格塘错全新世以来的古气候演化序列.10100 cal a BP兹格塘错地区进入全新世,全新世早中期为暖湿气候特征,在8600～8400和7400～7000 cal a BP发生两次强烈冷事件;中晚全新世以来气候变冷变干.这一气候演化过程与其邻近的错鄂的研究结果相近,代表了青藏高原中部全新世的气候演化特点.青藏高原中部全新世气候变化主要受太阳辐射控制.

Forecasting the effects of EU policy measures on the nitrate pollution of groundwater and surface waters

We used the interdisciplinary model network REGFLUD to predict the actual mean nitrate concentration in percolation water at the scale of the Weser river basin （Germany） using an area differentiated （100 m × 100 m） approach. REGFLUD combines the agro-economic model RAUMIS for estimating nitrogen surpluses and the hydrological models GROWA/DENUZ for assessing the nitrate leaching from the soil. For areas showing predicted nitrate concentrations in percolation water above the European Union （EU） groundwater quality standard of 50 mg NO3-N/L, effective agri-environmental reduction measures need to be derived and implemented to improve groundwater and surface water quality by 2015. The effects of already implemented agricultural policy are quantified by a baseline scenario projecting the N-surpluses from agricultural sector to 2015. The REGFLUD model is used to estimate the effects of this scenario concerning groundwater and surface water pollution by nitrate. From the results of the model analysis the needs for additional measures can be derived in terms of required additional N-surplus reduction and in terms of regional prioritization of measures. Research work will therefore directly support the implementation of the Water Framework Directive of the European Union in the Weser basin.

Hemispheric Specialization of the Primate Inferior Parietal Lobule

Hemispheric asymmetries can be seen as one of the evolutionary adaptations that allowed the human brain to muster more complex cognitive processes than other primates.In this vein,the study published by Cheng et al.[1]presents a pivotal investigation of both the regional and connectional asymmetries within the inferior parietal lobule(IPL)in human,chimpanzee,and macaque.By investigating 4 sub-divisions of the IPL across the three species,Cheng and colleagues showed that the macroanatomical and connectional architecture of the IPL became more asymmetric throughout the primate lineage.While macaques show little to no structural asymmetries,chimpanzees display a more asymmetric architecture but with both leftward and rightward asymmetries in various connections.In contrast,the human IPL displayed the highest number of asymmetries among the three species with a clear tendency towards more lateralization.This evolutionary trend towards a more lateralized organization of the IPL may have accompanied an improved command of tool-use,stronger forelimb asymmetries,and the increasing complexity of communicative behavior.