The development of a general approach for the nondestructive chemical and biological functionalization of graphene could expand opportunities for graphene in both fundamental studies and a variety of ...device platforms. Graphene is a delicate single-layer, two-dimensional network of carbon atoms whose properties can be affected by covalent modification. One method for functionalizing materials without fundamentally changing their inherent structure is using biorecognition moieties. In particular, oligopeptides are molecules containing a broad chemical diversity that can be achieved within a relatively compact size. Phage display is a dominant method for identifying peptides that possess enhanced selectivity toward a particular target. Here, we demonstrate a powerful yet benign approach for chemical functionalization of graphene via comprehensively screened phage displayed peptides. Our results show that graphene can be selectively recognized even in nanometer-defined strips. Further, modification of graphene with bifunctional peptides reveals both the ability to impart selective recognition of gold nanoparticles and the development of an ultrasensitive graphene-based TNT sensor. We anticipate that these results could open exciting opportunities in the use of graphene in fundamental biochemical recognition studies, as well as applications ranging from sensors to energy storage devices.
The rapid ascension of immune checkpoint blockade treatments has placed an emphasis on the need for viable, robust, and noninvasive imaging methods for immune checkpoint proteins, which could be of ...diagnostic value. Immunoconjugate-based positron emission tomography (immuno-PET) allows for sensitive and quantitative imaging of target levels and has promising potential for the noninvasive evaluation of immune checkpoint proteins. However, the advancement of immuno-PET is currently limited by available imaging tools, which heavily rely on full-length IgGs with Fc-mediated effects and are heterogeneous mixtures upon random conjugation with chelators for imaging. Herein, we have developed a site-specific αPD-L1 Fab conjugate with the chelator 1,4,7-triazacyclononane-N,N′,N″-triacetic acid (NOTA), enabling radiolabeling for PET imaging, using the amber suppression-mediated genetic incorporation of unnatural amino acid (UAA), p-azidophenylalanine. This Fab conjugate is homogeneous and demonstrated tight binding toward the PD-L1 antigen in vitro. The radiolabeled version, 64Cu-NOTA-αPD-L1, has been employed in PET imaging to allow for effective visualization and mapping of the biodistribution of PD-L1 in two normal mouse models, including the capturing of different PD-L1 expression levels in the spleens of the different mouse types. Follow-up in vivo blocking studies and ex vivo fluorescent staining further validated specific tissue uptakes of the imaging agent. This approach illustrates the utility of UAA-based site-specific Fab conjugation as a general strategy for making sensitive PET imaging probes, which could facilitate the elucidation of the roles of a wide variety of immune checkpoint proteins in immunotherapy.
As ecosystem engineers, seagrasses are angiosperms of paramount ecological importance in shallow shoreline habitats around the globe. Furthermore, the ancestors of independent seagrass lineages have ...secondarily returned into the sea in separate, independent evolutionary events. Thus, understanding the molecular adaptation of this clade not only makes significant contributions to the field of ecology, but also to principles of parallel evolution as well. With the use of Dr. Zompo, the first interactive seagrass sequence database presented here, new insights into the molecular adaptation of marine environments can be inferred. The database is based on a total of 14 597 ESTs obtained from two seagrass species, Zostera marina and Posidonia oceanica, which have been processed, assembled and comprehensively annotated. Dr. Zompo provides experimentalists with a broad foundation to build experiments and consider challenges associated with the investigation of this class of non-domesticated monocotyledon systems. Our database, based on the Ruby on Rails framework, is rich in features including the retrieval of experimentally determined heat-responsive transcripts, mining for molecular markers (SSRs and SNPs), and weighted key word searches that allow access to annotation gathered on several levels including Pfam domains, GeneOntology and KEGG pathways. Well established plant genome sites such as The Arabidopsis Information Resource (TAIR) and the Rice Genome Annotation Project are interfaced by Dr. Zompo. With this project, we have initialized a valuable resource for plant biologists in general and the seagrass community in particular. The database is expected to grow together with more data to come in the near future, particularly with the recent initiation of the Zostera genome sequencing project.The Dr. Zompo database is available at http://drzompo.uni-muenster.de/
Genetic incorporation of unnatural amino acids (UAAs) provides a unique approach to the synthesis of site-specific antibody conjugates that are homogeneous and better defined constructs than random ...conjugates. Yet, the yield varies for every antibody, and the process is costly and time-consuming. We have developed a switchable αGCN4-Fab conjugate that incorporates UAA p-acetylphenylalanine. The GCN4 peptide is used as a switch, and antibodies fused by GCN4 can direct the αGCN4-Fab conjugate to target different cancer cells for diagnosis, imaging, or therapeutic treatment. More importantly, this switchable conjugate demonstrated an impressive potential for pretargeted imaging in vivo. This approach illustrates the utility of an orthogonal switch as a general strategy to endow versatility to a single antibody conjugate, which should facilitate the application of UAA-based site-specific conjugates for a host of biomedical uses in the future.
Synthetic glucocorticoids (GC) are essential for the treatment of a broad range of inflammatory diseases. However, their use is limited by target related adverse effects on, e.g., glucose homeostasis ...and bone metabolism. Starting from a nonsteroidal GR ligand (4) that is a full agonist in reporter gene assays, we exploited key functional triggers within the receptor, generating a range of structurally diverse partial agonists. Of these, only a narrow subset exhibited full anti-inflammatory efficacy and a significantly reduced impact on adverse effect markers in human cell assays compared to prednisolone. This led to the discovery of AZD9567 (15) with excellent in vivo efficacy when dosed orally in a rat model of joint inflammation. Compound 15 is currently being evaluated in clinical trials comparing the efficacy and side effect markers with those of prednisolone.
Be Careful What You Ask For Marti, Mollie W; Wissler, Roselle L
Journal of experimental psychology. Applied
6, Številka:
2
Journal Article
Recenzirano
These studies examined the effects of anchors in the context of personal injury damages awards. In 2 experiments, mock jurors read a case in which the presence and size of the plaintiff's damages ...request and the defense rebuttal were varied across conditions and then awarded damages. Award size and variability increased as the plaintiff's request increased but decreased with the most extreme request. Conversely, award size and variability decreased as the defense rebuttal decreased but increased with the most extreme rebuttal. In both studies, the award recommendations altered the upper and lower boundaries of awards mock jurors found acceptable but did not affect mock jurors' perception of injury severity. The findings suggest that award recommendations can produce biased and unpredictable awards.
During the Late Barremian and Early Aptian (about 120 million years ago) intense volcanic degassing and extremely rapid release of methane hydrates contained in marine sediments added high amounts of ...carbon to the ocean and atmosphere, and resulted most probably in rising atmospheric carbon dioxide pressure. In order to document the response of the shallow water carbonate-producing communities to this pronounced disturbance of the carbon cycle we studied a Late Barremian to Early Aptian neritic carbonate succession deposited on the northern Tethyan shelf (Swiss Alps). The sedimentological and stable carbon and oxygen isotope records of two sections located along a N–S transect from proximal to more distal shelf environments were investigated. The sediments correspond to outer-, mid-, and inner-ramp deposits of a homoclinal carbonate ramp. Vertical facies variations within the two studied sections feature three progradation phases of the platform. A highly resolved correlation of the shelf sediments with a pelagic succession from the Southern Alps (Northern Italy) is based on both δ
13C stratigraphy and biostratigraphy, and indicates that the drowning of the Helvetic carbonate platform coincided with a pronounced calcification crisis of calcareous nannofossils. The biocalcification crisis started before but culminated during the Aptian methane event recorded in a negative carbon-isotope spike. We propose that increased carbon dioxide concentrations in oceans and atmosphere related to volcanic activity and to sudden methane release reduced the marine calcium carbonate oversaturation and the calcification potential of benthic and planktonic organisms. Carbonate-producing shallow water communities on platforms and ramps suffering from additional environmental stress such as extreme temperatures or high nutrient levels could not survive during times of rising sea level, and, as a consequence, carbonate platforms drowned.
Genomes of eusocial insects code for dramatic examples of phenotypic plasticity and social organization. We compared the genomes of seven ants, the honeybee, and various solitary insects to examine ...whether eusocial lineages share distinct features of genomic organization. Each ant lineage contains ∼4000 novel genes, but only 64 of these genes are conserved among all seven ants. Many gene families have been expanded in ants, notably those involved in chemical communication (e.g., desaturases and odorant receptors). Alignment of the ant genomes revealed reduced purifying selection compared with Drosophila without significantly reduced synteny. Correspondingly, ant genomes exhibit dramatic divergence of noncoding regulatory elements; however, extant conserved regions are enriched for novel noncoding RNAs and transcription factor-binding sites. Comparison of orthologous gene promoters between eusocial and solitary species revealed significant regulatory evolution in both cis (e.g., Creb) and trans (e.g., fork head) for nearly 2000 genes, many of which exhibit phenotypic plasticity. Our results emphasize that genomic changes can occur remarkably fast in ants, because two recently diverged leaf-cutter ant species exhibit faster accumulation of species-specific genes and greater divergence in regulatory elements compared with other ants or Drosophila. Thus, while the "socio-genomes" of ants and the honeybee are broadly characterized by a pervasive pattern of divergence in gene composition and regulation, they preserve lineage-specific regulatory features linked to eusociality. We propose that changes in gene regulation played a key role in the origins of insect eusociality, whereas changes in gene composition were more relevant for lineage-specific eusocial adaptations.
Over the past decade, the structure of the first formal mediation session has changed, with fewer traditional joint opening sessions and more separate caucuses to start the mediation. In light of ...these changes, the present Article explores whether mediators still see these two approaches as having the benefits conventionally ascribed to them, or whether they now see different advantages for each approach. The survey responses of over 700 experienced civil and family mediators from eight states show that mediators see several major differences in what can be better achieved in initial joint sessions and initial separate caucuses, respectively. Consistent with conventional wisdom, mediators said that initial joint sessions allow the parties to speak directly to and be heard by each other, and to develop a better understanding of the mediation process and the dispute, while initial separate caucuses permit the mediation to proceed when the parties are unable to mediate together civilly or meaningfully. Mediators noted multiple additional benefits associated with both parties hearing the same information at the same time in initial joint sessions, which previously have received little comment in the literature. Interestingly, mediators ascribed several other benefits to both initial joint sessions and initial separate caucuses, though generally for different reasons. Civil and family mediators differed in how often they mentioned some of the benefits for each approach. The present findings may encourage mediators and mediation trainers to revisit their views about the benefits they typically associate with initial joint sessions and initial separate caucuses and to weigh a broader set of considerations with the parties and lawyers when deciding how to begin the initial mediation session, allowing them to better tailor the mediation process to the needs of the particular case.
Research examining the relative effectiveness of mediation and adjudication has raised questions about whether the apparent benefits of mediation can be attributed to differences in the two dispute ...resolution procedures or, instead, are due to differences in the characteristics of the disputes or disputants. Litigants in four small claims courts provided multiple comparison groups that enabled us to examine case and process effects. Disputes and disputants in mediation and adjudication differed on few attributes. The process, outcomes, and impact of mediation and adjudication differed in ways generally consistent with their theoretical differences. Although the degree of liability admitted by the defendant played a role, overall, differences in the effectiveness of mediation and adjudication were due more to differences in the processes themselves than to differences in the disputes and disputants using each procedure.
PDF
