Determining Structures of Layer-by-Layer Spin-Coated Zinc Dicarboxylate-Based Metal-Organic Thin Films.

Thin films of crystalline solids with substantial free volume built from organic chromophores and metal secondary building units (SBUs) are promising for engineering new optoelectronic properties through control of interchromophore coupling. Zn-based SBUs are especially relevant in this case because they avoid quenching the chromophore's luminescence. We find that layer-by-layer spin-coating using Zn acetate dihydrate and benzene-1,4-dicarboxylic acid (H2BDC) and biphenyl-4,4'-dicarboxylic acid (H2BPDC) linkers readily produces crystalline thin films. However, analysis of the grazing-incidence wide-angle X-ray scattering (GIWAXS) data reveals the structures of these films vary significantly with the linker, and with the metal-to-linker molar ratio used for fabrication. Under equimolar conditions, H2BPDC creates a type of structure like that proposed for SURMOF-2, whereas H2BDC generates a different metal-hydroxide-organic framework. Large excess of Zn2+ ions causes the growth of layered zinc hydroxides, irrespective of the linker used. Density functional theory (DFT) calculations provide structural models with minimum total energy that are consistent with the experimentally observed diffractograms. In the broader sense, this work illustrates the importance in this field of careful structure determination, e. g., by utilizing GIWAXS and DFT simulations to determine the structure of the obtained crystalline metal-organic thin films, such that properties can be rationally engineered and explained.

Human-specific ARHGAP11B ensures human-like basal progenitor levels in hominid cerebral organoids.

The human-specific gene ARHGAP11B has been implicated in human neocortex expansion. However, the extent of ARHGAP11B's contribution to this expansion during hominid evolution is unknown. Here we address this issue by genetic manipulation of ARHGAP11B levels and function in chimpanzee and human cerebral organoids. ARHGAP11B expression in chimpanzee cerebral organoids doubles basal progenitor levels, the class of cortical progenitors with a key role in neocortex expansion. Conversely, interference with ARHGAP11B's function in human cerebral organoids decreases basal progenitors down to the chimpanzee level. Moreover, ARHGAP11A or ARHGAP11B rescue experiments in ARHGAP11A plus ARHGAP11B double-knockout human forebrain organoids indicate that lack of ARHGAP11B, but not of ARHGAP11A, decreases the abundance of basal radial glia-the basal progenitor type thought to be of particular relevance for neocortex expansion. Taken together, our findings demonstrate that ARHGAP11B is necessary and sufficient to ensure the elevated basal progenitor levels that characterize the fetal human neocortex, suggesting that this human-specific gene was a major contributor to neocortex expansion during human evolution.

De novo PHF5A variants are associated with craniofacial abnormalities, developmental delay, and hypospadias.

PURPOSE: The SF3B splicing complex is composed of SF3B1-6 and PHF5A. We report a developmental disorder caused by de novo variants in PHF5A. METHODS: Clinical, genomic, and functional studies using subject-derived fibroblasts and a heterologous cellular system were performed. RESULTS: We studied 9 subjects with congenital malformations, including preauricular tags and hypospadias, growth abnormalities, and developmental delay who had de novo heterozygous PHF5A variants, including 4 loss-of-function (LOF), 3 missense, 1 splice, and 1 start-loss variant. In subject-derived fibroblasts with PHF5A LOF variants, wild-type and variant PHF5A mRNAs had a 1:1 ratio, and PHF5A mRNA levels were normal. Transcriptome sequencing revealed alternative promoter use and downregulated genes involved in cell-cycle regulation. Subject and control fibroblasts had similar amounts of PHF5A with the predicted wild-type molecular weight and of SF3B1-3 and SF3B6. SF3B complex formation was unaffected in 2 subject cell lines. CONCLUSION: Our data suggest the existence of feedback mechanisms in fibroblasts with PHF5A LOF variants to maintain normal levels of SF3B components. These compensatory mechanisms in subject fibroblasts with PHF5A or SF3B4 LOF variants suggest disturbed autoregulation of mutated splicing factor genes in specific cell types, that is, neural crest cells, during embryonic development rather than haploinsufficiency as pathomechanism.

Rational design of highly stabilized and selective adrenomedullin analogs.

The peptide hormone adrenomedullin (ADM) consists of 52 amino acids with a disulfide bond and an amidated C-terminus. Due to the vasodilatory and cardioprotective effects, the agonistic activity of the peptide on the adrenomedullin 1 receptor (AM1 R) is of high pharmacological interest. However, the wild-type peptide shows low metabolic stability leading to rapid degradation in the cardiovascular system. Previous work by our group has identified proteolytic cleavage sites and demonstrated stabilization of ADM by lipidation, cyclization, and N-methylation. Nevertheless, these ADM analogs showed reduced activity and subtype selectivity toward the closely related calcitonin gene-related peptide receptor (CGRPR). Here, we report on the rational development of ADM derivatives with increased proteolytic stability and high receptor selectivity. Stabilizing motifs, including lactamization and lipidation, were evaluated regarding AM1 R and CGRPR activation. Furthermore, the central DKDK motif of the peptide was replaced by oligoethylene glycol linkers. The modified peptides were synthesized by Fmoc/t-Bu solid-phase peptide synthesis and receptor activation of AM1 R and CGRPR was measured by cAMP reporter gene assay. Peptide stability was tested in human blood plasma and porcine liver homogenate and analyzed by RP-HPLC and MALDI-ToF mass spectrometry. Combination of the favorable lactam, lipidation, ethylene glycol linker, and previously described disulfide mimetic resulted in highly stabilized analogs with a plasma half-life of more than 144 h. The compounds display excellent AM1 R activity and wild-type-like selectivity toward CGRPR. Additionally, dose-dependent vasodilatory effects of the ADM derivatives lasted for several hours in rodents. Thus, we successfully developed an ADM analog with long-term in vivo activity.

A neural network for tics: insights from causal brain lesions and deep brain stimulation.

Brain lesions are a rare cause of tic disorders. However, they can provide uniquely causal insights into tic pathophysiology and can also inform on possible neuromodulatory therapeutic targets. Based on a systematic literature review, we identified 22 cases of tics causally attributed to brain lesions and employed 'lesion network mapping' to interrogate whether tic-inducing lesions would be associated with a common network in the average human brain. We probed this using a normative functional connectome acquired in 1000 healthy participants. We then examined the specificity of the identified network by contrasting tic-lesion connectivity maps to those seeding from 717 lesions associated with a wide array of neurological and/or psychiatric symptoms within the Harvard Lesion Repository. Finally, we determined the predictive utility of the tic-inducing lesion network as a therapeutic target for neuromodulation. Specifically, we collected retrospective data of 30 individuals with Tourette disorder, who underwent either thalamic (n = 15; centromedian/ventrooralis internus) or pallidal (n = 15; anterior segment of globus pallidus internus) deep brain stimulation and calculated whether connectivity between deep brain stimulation sites and the lesion network map could predict clinical improvements. Despite spatial heterogeneity, tic-inducing lesions mapped to a common network map, which comprised the insular cortices, cingulate gyrus, striatum, globus pallidus internus, thalami and cerebellum. Connectivity to a region within the anterior striatum (putamen) was specific to tic-inducing lesions when compared with control lesions. Connectivity between deep brain stimulation electrodes and the lesion network map was predictive of tic improvement, regardless of the deep brain stimulation target. Taken together, our results reveal a common brain network involved in tic generation, which shows potential as a therapeutic target for neuromodulation.

Tunable J-type aggregation of silicon phthalocyanines in a surface-anchored metal-organic framework thin film.

Organic chromophores and semiconductors, like anthracene, pentacene, perylene, and porphyrin, are prone to aggregation, and their packing in the solid state is often hard to predict and difficult to control. As the condensed phase structures of these chromophores and semiconductors are of crucial importance for their optoelectronic functionality, strategies to control their assembly and provide new structural motifs are important. One such approach uses metal-organic frameworks (MOFs); the organic chromophore is converted into a linker and connected by metal ions or nodes. The spatial arrangement of the organic linkers can be well-defined in a MOF, and hence optoelectronic functions can be adjusted accordingly. We have used such a strategy to assemble a phthalocyanine chromophore and illustrated that the electronic inter-phthalocyanine coupling can be rationally tuned by introducing bulky side grounds to increase steric hindrance. We have designed new phthalocyanine linkers and using a layer-by-layer liquid-phase epitaxy strategy thin films of phthalocyanine-based MOFs have been fabricated and their photophysical properties explored. It was found that increasing the steric hindrance around the phthalocyanine reduced the effect of J-aggregation in the thin film structures.

Comparison of Chemical and Electrochemical Approaches to Abacavir Oxidative Stability Testing.

A novel electrochemical approach using two different electrode materials, platinum and boron-doped diamond (BDD), was employed to study the oxidative stability of the drug abacavir. Abacavir samples were subjected to oxidation and subsequently analysed using chromatography with mass detection. The type and amount of degradation products were evaluated, and results were compared with traditional chemical oxidation using 3% hydrogen peroxide. The effect of pH on the rate of degradation and the formation of degradation products were also investigated. In general, both approaches led to the same two degradation products, identified using mass spectrometry, and characterised by 319.20 and m/z 247.19. Similar results were obtained on a large-surface platinum electrode at a potential of +1.15 V and a BDD disc electrode at +4.0 V. Degradation of 20% of abacavir, the rate required for pharmaceutical stability studies, took only a few minutes compared to hours required for oxidation with hydrogen peroxide. Measurements further showed that electrochemical oxidation in ammonium acetate on both types of electrodes is strongly pHdependent. The fastest oxidation was achieved at pH 9. The pH also affects the composition of the products, which are formed in different proportions depending on the pH of the electrolyte.

The Effect of Sample Pretreatment on the Anthocyanin Content in Czech Wild Elderberry (Sambucus nigra L.).

This work focusses on the analysis of anthocyanins present in wild Czech elderberries, using spectrophotometric methods and liquid chromatography. Spectrophotometric methods were used to determine antioxidant capacity, total phenolic content, and total anthocyanin content. Further, four major elderberry anthocyanins were determined using reversed-phase high-performance liquid chromatography with isocratic elution of 30% aqueous methanol with 5% of formic acid. All optimised methods were applied to the analysis of extracts prepared from frozen and dried elderberry fruit samples, and the results were evaluated using principal component analysis which clearly divided the samples into individual groups according to the sample pretreatment (frozen and dried samples). The frozen samples reached higher values of antioxidant capacity and total phenolic and anthocyanin contents compared to the dried samples, probably due to the degradation of anthocyanins during the drying process.

The recurrent TCF4 missense variant p.(Arg389Cys) causes a neurodevelopmental disorder overlapping with but not typical for Pitt-Hopkins syndrome.

TCF4 haploinsufficiency by deletions, truncating variants or loss-of-function missense variants within the DNA-binding and protein interacting bHLH domain causes Pitt-Hopkins syndrome (PTHS). This neurodevelopmental disorder (NDD) is characterized by severe intellectual disability (ID), epilepsy, hyperbreathing and a typical facial gestalt. Only few aberrations of the N-terminus of TCF4 were associated with milder or atypical phenotypes. By personal communication and searching databases we assembled six cases with the novel, recurrent, de novo missense variant c.1165C > T, p.(Arg389Cys) in TCF4. This variant was identified by diagnostic exome or panel sequencing and is located upstream of the bHLH domain. All six individuals presented with moderate to severe ID with language impairment. Microcephaly occurred in two individuals, epilepsy only in one, and no breathing anomalies or myopia were reported. Facial gestalt showed some aspects of PTHS but was rather non-specific in most individuals. Interestingly, the variant is located within the AD2 activation domain next to a highly conserved coactivator-recruitment motif and might alter interaction with coactivator proteins independently from the bHLH domain. Our findings of a recurrent missense variant outside the bHLH domain in six individuals with an ID phenotype overlapping with but not typical for PTHS delineate a novel genotype-phenotype correlation for TCF4-related NDDs.

Device for respiration activity measurement enables the determination of oxygen transfer rates of microbial cultures in shaken 96-deepwell microtiter plates.

Mini-bioreactors with integrated online monitoring capabilities are well established in the early stages of process development. Mini-bioreactors fulfil the demand for high-throughput-applications and a simultaneous reduction of material costs and total experimental time. One of the most essential online monitored parameters is the oxygen transfer rate (OTR). OTR-monitoring allows fast characterization of bioprocesses and process transfer to larger scales. Currently, OTR-monitoring on a small-scale is limited to shake flasks and 48-well microtiter plates (MTP). Especially, 96-deepwell MTP are used for high-throughput-experiments during early-stage bioprocess development. However, a device for OTR monitoring in 96-deepwell MTP is still not available. To determine OTR values, the measurement of the gas composition in each well of a MTP is necessary. Therefore, a new micro(µ)-scale Transfer rate Online Measurement device (µTOM) was developed. The µTOM includes 96 parallel oxygen-sensitive sensors and a single robust sealing mechanism. Different organisms (Escherichia coli, Hansenula polymorpha, and Ustilago maydis) were cultivated in the µTOM. The measurement precision for 96 parallel cultivations was 0.21 mmol·L-1 ·h-1 (pooled standard deviation). In total, a more than 15-fold increase in throughput and an up to a 50-fold decrease in media consumption, compared with the shake flask RAMOS-technology, was achieved using the µTOM for OTR-monitoring.

Revisiting the chondrichthyan egg capsules inventory from the Pennsylvanian (Carboniferous) of Belgium: new data and perspectives.

Records of chondrichthyan egg capsule morphotypes from the paralic deposits of the Belgian Coal Measures Group (Pennsylvanian; Bashkirian-Moscovian; Namurian B-Westphalian B according to the traditional subdivision) are presented and discussed. These include several species of the hybodontiform type Palaeoxyris as well as the putative holocephalian types Vetacapsula and Crookallia. Furthermore, the type specimens of Scapellites cottoni and S. minor, two additional putative and enigmatic egg capsules from the same lithostratigraphic unit, are figured and discussed. Altogether, a highly diverse egg capsule assemblage documented from the Belgian deposits implies the presence of at least eleven different Carboniferous chondrichthyan species using the ancient aquatic environments for spawning and as nurseries. The absence of the xenacanthiform morphotype Fayolia, known from surrounding coeval Coal Measures areas of northern France, the Netherlands, and Germany, is conspicuous. This lack may be a result of collecting bias and does not reflect a real pattern.

BODIPY-pyrene donor-acceptor sensitizers for triplet-triplet annihilation upconversion: the impact of the BODIPY-core on upconversion efficiency.

Triplet-triplet annihilation upconversion (TTA-UC) is an important type of optical process with applications in biophotonics, solar energy harvesting and photochemistry. In most of the TTA-UC systems, the formation of triplet excited states takes place via spin-orbital interactions promoted by heavy atoms. Given the crucial role of heavy atoms (especially noble metals, such as Pd and Pt) in promoting intersystem crossing (ISC) and, therefore, in production of UC luminescence, the feasibility of using more readily available and inexpensive sensitizers without heavy atoms remains a challenge. Here, we investigated sensitization of TTA-UC using BODIPY-pyrene heavy-atom-free donor-acceptor dyads with different numbers of alkyl groups in the BODIPY scaffold. The molecules with four and six alkyl groups are unable to sensitize TTA-UC in the investigated solvents (tetrahydrofuran (THF) and dichloromethane (DCM)) due to negligible ISC. In contrast, the dyad with two methyl groups in the BODIPY scaffold and the dyad with unsubstituted BODIPY demonstrate efficient intersystem crossing (ISC) of 49-58%, resulting in TTA-UC with quantum yields of 4.7% and 6.9%, respectively. The analysis of the elementary steps of the TTA-UC process indicates that heavy-atom-free donor-acceptor dyads are less effective than their noble metal counterparts, but may equal them in the future if the right combination of solvent, donor-acceptor sensitizer structure, and new luminescent molecules as TTA-UC emitters can be found.

[Promoting autonomy in the field of open child and youth work-results from a participatory evaluation project]. / Autonomie in der Offenen Kinder- und Jugendarbeit fördern ­ Ergebnisse eines partizipativen Evaluationsprojekts.

BACKGROUND: Facilitating participation is part of the mandate of open child and youth work. This also means youths have a voice in the development of youth center offerings. The participatory health research approach can support accomplishing this mandate. OBJECTIVES: As a consequence of the municipal youth congress's demand for more autonomy so-called "Autonomous Openings" (AO) - the opening of youth centers by the youths themselves and spending their time independently - were implemented in Braunschweig, Germany. Participatory research methods were used to scientifically support the center's youths and professionals in evaluating the AOs. This paper reports on one of three contributing youth centers. STUDY DESIGN AND SETTING: After each AO the adolescents reflected on their experiences by filling in a questionnaire jointly developed by researchers and professionals. The survey was accessible via the digital tool "Mentimeter". The professionals' perspective was captured in interviews. Topics such as revealing one's personal interests and the development of competencies were the main interest. The gathered data was assessed by the researchers and reflected upon together with youths and professionals during a workshop. RESULTS: Ten AOs took place throughout a period of ten months. Five adolescents were preliminary responsible and about another 20 were co-responsible. The results show that young people revealed their own interests more substantially. Moreover, the professionals observed a strengthening of competencies in various fields. Several factors were identified that can facilitate transferability to other youth centers. Reliable relationships that enable a trusting and equal exchange between professionals and youths are essential.

Natural Glycoforms of Human Interleukin 6 Show Atypical Plasma Clearance.

A library of glycoforms of human interleukin 6 (IL-6) comprising complex and mannosidic N-glycans was generated by semisynthesis. The three segments were connected by sequential native chemical ligation followed by two-step refolding. The central glycopeptide segments were assembled by pseudoproline-assisted Lansbury aspartylation and subsequent enzymatic elongation of complex N-glycans. Nine IL-6 glycoforms were synthesized, seven of which were evaluated for in vivo plasma clearance in rats and compared to non-glycosylated recombinant IL-6 from E. coli. Each IL-6 glycoform was tested in three animals and reproducibly showed individual serum clearances depending on the structure of the N-glycan. The clearance rates were atypical, since the 2,6-sialylated glycoforms of IL-6 cleared faster than the corresponding asialo IL-6 with terminal galactoses. Compared to non-glycosylated IL-6 the plasma clearance of IL-6 glycoforms was delayed in the presence of larger and multibranched N-glycans in most cases.

FHL-1 is not involved in pressure overload-induced maladaptive right ventricular remodeling and dysfunction.

AIMS: The cytoskeletal signaling protein four and-a-half LIM domains 1 (FHL-1) has recently been identified as a novel key player in pulmonary hypertension as well as in left heart diseases. In this regard, FHL-1 has been implicated in dysregulated hypertrophic signaling in pulmonary arterial smooth muscle cells leading to pulmonary hypertension. In mice, FHL-1-deficiency (FHL-1-/-) led to an attenuated hypertrophic signaling associated with a blunted hypertrophic response of the pressure-overloaded left ventricle (LV). However, the role of FHL-1 in right heart hypertrophy has not yet been addressed. METHODS AND RESULTS: We investigated FHL-1 expression in C57Bl/6 mice subjected to chronic biomechanical stress and found it to be enhanced in the right ventricle (RV). Next, we subjected FHL-1-/- and corresponding wild-type mice to pressure overload of the RV by pulmonary arterial banding for various time points. However, in contrast to the previously published study in LV-pressure overload, which was confirmed here, RV hypertrophy and hypertrophic signaling was not diminished in FHL-1-/- mice. In detail, right ventricular pressure overload led to hypertrophy, dilatation and fibrosis of the RV from both FHL-1-/- and wild-type mice. RV remodeling was associated with impaired RV function as evidenced by reduced tricuspid annular plane systolic excursion. Additionally, PAB induced upregulation of natriuretic peptides and slight downregulation of phospholamban and ryanodine receptor 2 in the RV. However, there was no difference between genotypes in the degree of expression change. CONCLUSION: FHL-1 pathway is not involved in the control of adverse remodeling in the pressure overloaded RV.

Self-injurious behaviour in movement disorders: systematic review.

Self-injurious behaviours (SIBs) are defined as deliberate, repetitive and persistent behaviours that are directed towards the body and lead to physical injury and are not associated with sexual arousal and without suicidal intent. In movement disorders, SIBs are typically associated with tic disorders, most commonly Tourette syndrome, and neurometabolic conditions, such as classic Lesch-Nyhan syndrome. However, beyond these well-known aetiologies, a range of other movement disorder syndromes may also present with SIBs, even though this clinical association remains less well-known. Given the scarcity of comprehensive works on this topic, here we performed a systematic review of the literature to delineate the spectrum of movement disorder aetiologies associated with SIBs. We report distinct aetiologies, which are clustered in five different categorical domains, namely, neurodevelopmental, neurometabolic and neurodegenerative disorders, as well as disorders with characteristic structural brain changes and heterogeneous aetiologies (eg, autoimmune and drug-induced). We also provide insights in the pathophysiology of SIBs in these patients and discuss neurobiological key risk factors, which may facilitate their manifestation. Finally, we provide a list of treatments, including practical measures, such as protective devices, as well as behavioural interventions and pharmacological and neurosurgical therapies.

The C-terminal domain of p53 orchestrates the interplay between non-covalent and covalent poly(ADP-ribosyl)ation of p53 by PARP1.

The post-translational modification poly(ADP-ribosyl)ation (PARylation) plays key roles in genome maintenance and transcription. Both non-covalent poly(ADP-ribose) binding and covalent PARylation control protein functions, however, it is unknown how the two modes of modification crosstalk mechanistically. Employing the tumor suppressor p53 as a model substrate, this study provides detailed insights into the interplay between non-covalent and covalent PARylation and unravels its functional significance in the regulation of p53. We reveal that the multifunctional C-terminal domain (CTD) of p53 acts as the central hub in the PARylation-dependent regulation of p53. Specifically, p53 bound to auto-PARylated PARP1 via highly specific non-covalent PAR-CTD interaction, which conveyed target specificity for its covalent PARylation by PARP1. Strikingly, fusing the p53-CTD to a protein that is normally not PARylated, renders this a target for covalent PARylation as well. Functional studies revealed that the p53-PAR interaction had substantial implications on molecular and cellular levels. Thus, PAR significantly influenced the complex p53-DNA binding properties and controlled p53 functions, with major implications on the p53-dependent interactome, transcription, and replication-associated recombination. Remarkably, this mechanism potentially also applies to other PARylation targets, since a bioinformatics analysis revealed that CTD-like regions are highly enriched in the PARylated proteome.

mGEODAR-A Mobile Radar System for Detection and Monitoring of Gravitational Mass-Movements.

Radar measurements of gravitational mass-movements like snow avalanches have become increasingly important for scientific flow observations, real-time detection and monitoring. Independence of visibility is a main advantage for rapid and reliable detection of those events, and achievable high-resolution imaging proves invaluable for scientific measurements of the complete flow evolution. Existing radar systems are made for either detection with low-resolution or they are large devices and permanently installed at test-sites. We present mGEODAR, a mobile FMCW (frequency modulated continuous wave) radar system for high-resolution measurements and low-resolution gravitational mass-movement detection and monitoring purposes due to a versatile frequency generation scheme. We optimize the performance of different frequency settings with loop cable measurements and show the freespace range sensitivity with data of a car as moving point source. About 15 dB signal-to-noise ratio is achieved for the cable test and about 5 dB or 10 dB for the car in detection and research mode, respectively. By combining continuous recording in the low resolution detection mode with real-time triggering of the high resolution research mode, we expect that mGEODAR enables autonomous measurement campaigns for infrastructure safety and mass-movement research purposes in rapid response to changing weather and snow conditions.

Adrenomedullin disulfide bond mimetics uncover structural requirements for AM1 receptor activation.

Adrenomedullin (ADM) is a vasoactive peptide hormone of 52 amino acids and belongs to the calcitonin peptide superfamily. Its vasodilative effects are mediated by the interaction with the calcitonin receptor-like receptor (CLR), a class B G protein-coupled receptor (GPCR), associated with the receptor activity modifying protein 2 (RAMP2) and functionally described as AM-1 receptor (AM1 R). A disulfide-bonded ring structure consisting of six amino acids between Cys16 and Cys21 has been shown to be a key motif for receptor activation. However, the specific structural requirements remain to be elucidated. To investigate the influence of ring size and position of additional functional groups that replace the native disulfide bond, we generated ADM analogs containing thioether, thioacetal, alkane, and lactam bonds between amino acids 16 and 21 by Fmoc/t-Bu solid phase peptide synthesis. Activity studies of the ADM disulfide bond mimetics (DSBM) revealed a strong impact of structural parameters. Interestingly, an increased ring size was tolerated but the activity of lactam-based mimetics depended on its position within the bridging structure. Furthermore, we found the thioacetal as well as the thioether-based mimetics to be well accepted with full AM1 R activity. While a reduced selectivity over the calcitonin gene-related peptide receptor (CGRPR) was observed for the thioethers, the thioacetal was able to retain a wild-type-like selectivity profile. The carbon analog in contrast displayed weak antagonistic properties. These results provide insight into the structural requirements for AM1 R activation as well as new possibilities for the development of metabolically stabilized analogs for therapeutic applications of ADM.