The Hill equation and the origin of quantitative pharmacology

This review addresses the 100-year-old Hill equation (published in January 22, 1910), the first formula relating the result of a reversible association (e.g., concentration of a complex, magnitude of an effect) to the variable concentration of one of the associating substances (the other being present in a constant and relatively low concentration). In addition, the Hill equation was the first (and is the simplest) quantitative receptor model in pharmacology. Although the Hill equation is an empirical receptor model (its parameters have only physico-chemical meaning for a simple ligand binding reaction), it requires only minor a priori knowledge about the mechanism of action for the investigated agonist to reliably fit concentration-response curve data and to yield useful results (in contrast to most of the advanced receptor models). Thus, the Hill equation has remained an important tool for physiological and pharmacological investigations including drug discovery, moreover it serves as a theoretical basis for the development of new pharmacological models.     

Taxonomy and variation of the Lopidea nigridia complex of western North America (Heteroptera: Miridae, Orthotylinae)

External morphological variation in the Lopidea nigridia "complex" of western North America was examined using principal component analysis and showed continuous variation among populations in most characters. External morphology did not parallel paramere structure and did not substantiate previously recognized species. There was little correlation between dorsal coloration and paramere structure. Cluster analysis (UPGMA) using paramere and color characters failed to group populations coded as the same species and also failed to group all specimens of any one population. The variation in structure of the parameres and vesicae among populations of the nigridia complex was no greater than the interpopulational variation of these structures structures in the congeneric species marginata Uhler. Lopidea nigridia Uhler is treated as a polytypic species comprising three subspecies: Lopidea nigridia nigridia Uhler, a fuscous-white form from the sagebrush steppe of the Great Basin and the chaparral of southern California; Lopidea nigridia serica Knight, a solid red form from the eastern slopes of the Rocky Mountains from Alberta to Colorado and east across the Northern Great Plains to southern Manitoba; Lopidea nigridia aculeata Van Duzee, a polymorphic form varying from solid red to fuscous red and white from the Cascade Mountains and eastern slopes of the coastal ranges of British Columbia, Washington, and Oregon, the Blue and Wallawa mountains of Oregon and Washington, and throughout the Coastal and Sierra Nevada ranges of California. The following new synonymies are created: Lopidea nigridia Uhler -- Lopidea raineri Knight, Lopidea scullent Knight, Lopidea rolfsi Knight, and Lopidea wilcoxi Knight; Lopidea nigridia aculeata Van Duzee -- Lopidea nigridia hirta Van Duzee, Lopidea usingeri Van Duzee, Lopidea discreta Van Duzee, Lopidea fallax Knight, Lopidea Yakima Knight, Lopidea audeni Knight, Lopidea eriogoni Knight, Lopidea calcaria Knight, Lopidea chamberlini Knight, Lopidea angustata Knight, Lopidea rubrofusca Knight, and Lopidea flavicostata Knight and Schaffner; Lopidea nigridia serica Knight -- Lopidea medleri Akingbohungbe.     

The patterns and dynamics of genomic instability in metastatic pancreatic cancer

Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97-98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2-M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.     

A 61-million-person experiment in social influence and political mobilization

Human behaviour is thought to spread through face-to-face social networks, but it is difficult to identify social influence effects in observational studies, and it is unknown whether online social networks operate in the same way. Here we report results from a randomized controlled trial of political mobilization messages delivered to 61 million Facebook users during the 2010 US congressional elections. The results show that the messages directly influenced political self-expression, information seeking and real-world voting behaviour of millions of people. Furthermore, the messages not only influenced the users who received them but also the users' friends, and friends of friends. The effect of social transmission on real-world voting was greater than the direct effect of the messages themselves, and nearly all the transmission occurred between 'close friends' who were more likely to have a face-to-face relationship. These results suggest that strong ties are instrumental for spreading both online and real-world behaviour in human social networks.     

TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis

Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS), it has been difficult to demonstrate which variants are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance. Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.     

Delayed hypersensitivity and antibody response in rheumatoid arthritis

Zusammenfassung Es wird über die immunologische Reaktivität von Patienten mit progressiver Polyarthritis berichtet. Nach Injektion von 25 E Streptokinase (Präparat Dornokinase) zeigten die Patienten eine gewisse Dissoziation der immunologischen Vorgänge: Herabsetzung der Hautreaktionen und erhöhte spezifische Antikörperreaktion.