Synthesis and In-Vitro Cell Viability/Cytotoxicity Studies of Novel Pyrrolobenzodiazepine Derivatives

Pyrrolobenzodiazepines (PBDs) are a group of naturally occurring compounds that were discovered in the cultures of Streptomyces in the 1960s. Some natural PBDs discovered in these cultures, such as anthramycin and sibiromycin, were shown to possess a broad spectrum of anti-tumor activity. Since cancer is still a leading cause of death globally, the development of novel anti-proliferative derivatives of PBDs is essential for human welfare worldwide. Further synthesis and structure-activity relationship (SAR) studies of the parent natural products and their tetracyclic analogs will lead to the discovery of drug candidates. In this work, thirteen PBD analogues were synthesized using no more than three to four synthetic steps, beginning with commercially obtainable L-proline and isatoic anhydride. The MTT assay, which is a colorimetric assay that uses 3-(4,5-Dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) to assess cell metabolic activity, was initially implimented to test the in vitro cytotoxicity of the compounds using multiple cell lines, namely: SKBR-3, MCF-7, SKMEL-2, CaCo 2, HCT 116, and Mia Paca. Nearly all of the compounds decreased the cell viability of MCF-7 by roughly 20%. Additionally, the anti-proliferative activity of the PBD products were further evaluated by the NCI-60 Human Tumor Cell Lines Screen, which is a part of the National Cancer Institute’s Development Therapeutics Program - Drug Synthesis and Chemistry Branch

The Discovery of Trissolcus japonicus (Hymenoptera: Scelionidae) in Michigan

The invasive brown marmorated stink bug, Halyomorpha halys (Stål), is a pest of growing economic importance in the United States, the control of which currently relies on pesticide applications. Biological control could provide sustainable and long-term control but classical biological control agents have not yet been approved. Adventive populations of a potential biological control agents, the Samurai wasp, Trissolcus japonicus (Ashmead), have been found in the United States, first in Maryland in 2014, expanding its range west to Ohio by 2017. Trissolcus japonicus is a highly effective parasitoid of H. halys eggs, but its redistribution and augmentative releases are restricted to states where it has been detected in the wild. To assess the presence of T. japonicus in Michigan and attack rates of H. halys by native natural enemies we deployed 189 H. halys egg masses at ten sites in lower Michigan between May and October in 2018. In addition, we deployed 51 native stink bug egg masses at the same sites to evaluate potential non-target effects of T. japonicus in the field, which were shown to occur in laboratory studies. We found T. japonicus in a single H. halys egg mass, which constitutes the first record of this Asian parasitoid in Michigan. Native predators and parasitoids caused minimal mortality of H. halys eggs and we did not find evidence of non-target effects of T. japonicus on native stink bug species. These findings open the door to initiation of a classical biological control program using an efficient, coevolved parasitoid from the native range of H. halys

Groups of Galaxies in the Two Micron All-Sky Redshift Survey

We present the results of applying a percolation algorithm to the initial release of the Two Micron All-Sky Survey Extended Source Catalog, using subsequently measured redshifts for almost all of the galaxies with K < 11.25 mag. This group catalog is based on the first near-IR all-sky flux-limited survey that is complete to |b| = 5 deg. We explore the dependence of the clustering on the length and velocity scales involved. The paper describes a group catalog, complete to a limiting redshift of 10,000 km/s, created by maximizing the number of groups containing 3 or more members. A second catalog is also presented, created by requiring a minimum density contrast of 80 to identify groups. We identify known nearby clusters in the catalogs and contrast the groups identified in the two catalogs. We examine and compare the properties of the determined groups and verify that the results are consistent with the UZC-SSRS2 and northern CfA redshift survey group catalogs. The all-sky nature of the catalog will allow the development of a flow-field model based on the density field inferred from the estimated cluster masses.Comment: Accepted for publication in ApJ (29 pages including 13 figures). A version with high-resolution figures is available at http://www.cfa.harvard.edu/~acrook/preprints

Divergence of cAMP Signalling Pathways Mediating Augmented Nucleotide Excision Repair and Pigment Induction in Melanocytes

Loss‐of‐function melanocortin 1 receptor (MC1R) polymorphisms are common in UV‐sensitive fair‐skinned individuals and are associated with blunted cAMP second messenger signalling and higher lifetime risk of melanoma because of diminished ability of melanocytes to cope with UV damage. cAMP signalling positions melanocytes to resist UV injury by upregulating synthesis of UV‐blocking eumelanin pigment and by enhancing the repair of UV‐induced DNA damage. cAMP enhances melanocyte nucleotide excision repair (NER), the genome maintenance pathway responsible for the removal of mutagenic UV photolesions, through cAMP‐activated protein kinase (protein kinase A)‐mediated phosphorylation of the ataxia telangiectasia‐mutated and Rad3‐related (ATR) protein on the S435 residue. We investigated the interdependence of cAMP‐mediated melanin upregulation and cAMP‐enhanced DNA repair in primary human melanocytes and a melanoma cell line. We observed that the ATR‐dependent molecular pathway linking cAMP signalling to the NER pathway is independent of MITF activation. Similarly, cAMP‐mediated upregulation of pigment synthesis is independent of ATR, suggesting that the key molecular events driving MC1R‐mediated enhancement of genome maintenance (eg PKA‐mediated phosphorylation of ATR) and MC1R‐induced pigment induction (eg MITF activation) are distinct

The Discovery of Trissolcus japonicus (Hymenoptera: Scelionidae) in Michigan

The invasive brown marmorated stink bug, Halyomorpha halys (Stål), is a pest of growing economic importance in the United States, the control of which currently relies on pesticide applications. Biological control could provide sustainable and long-term control but classical biological control agents have not yet been approved. Adventive populations of a potential biological control agents, the Samurai wasp, Trissolcus japonicus (Ashmead), have been found in the United States, first in Maryland in 2014, expanding its range west to Ohio by 2017. Trissolcus japonicus is a highly effective parasitoid of H. halys eggs, but its redistribution and augmentative releases are restricted to states where it has been detected in the wild. To assess the presence of T. japonicus in Michigan and attack rates of H. halys by native natural enemies we deployed 189 H. halys egg masses at ten sites in lower Michigan between May and October in 2018. In addition, we deployed 51 native stink bug egg masses at the same sites to evaluate potential non-target effects of T. japonicus in the field, which were shown to occur in laboratory studies. We found T. japonicus in a single H. halys egg mass, which constitutes the first record of this Asian parasitoid in Michigan. Native predators and parasitoids caused minimal mortality of H. halys eggs and we did not find evidence of non-target effects of T. japonicus on native stink bug species. These findings open the door to initiation of a classical biological control program using an efficient, coevolved parasitoid from the native range of H. halys

Synthesis and Biological Activity of Fused tetracyclic Pyrrolo[2,1-C][1,4]Benzodiazepines

Cancer remains the second major cause of death in the world. Thus, there is a pressing need to identify potential synthetic route for the development of novel anticancer agents which will serve as lead compounds to effectively combat this life-threatening epidemic. Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) have sparked a great interest as lead compounds because of their cancerostatic and anti-infective properties. The twisted molecular structure of PBD analogs provides both helical and chiral elements. In an effort to expand novel PBDs that interact with the key exocyclic amino group of the DNA-guanine base, we hypothesized that construction of a fused cyclic active system, would likely serve as an electrophilic site when compared to traditional electrophilic C11-N10 imine group. To examine our theory, we report herein the synthesis and cell viability/cytotoxicity of a series of PBD analogs using NCI-60 cell lines screening. Thus, compounds 1–13 were synthesized and fully characterized. The selected PBDs were found to have marginal inhibition of growth, up to 30%, for certain cell lines

Myths about autism: an exploratory study using focus groups

Individuals with autism are often stigmatised and isolated by their typically developing peers according to parental, teacher and self-reports. Whilst quantitative studies often report negative attitudes towards individuals with autism, it is still unclear how understandings of autism influence attitudes. In this exploratory study, misconceptions or myths about autism, i.e. the cognitive component of attitudes, were examined using focus groups. Purposive sampling was used to recruit undergraduate and postgraduate students, and adults with and without experience of autism, to one of five focus groups (n = 37). Content analysis was used to identify emergent themes. The data identified seven commonly held beliefs about individuals with autism. The first four were related to social interaction, such as that people with autism do not like to be touched. The fifth reflected the view that all individuals with autism have a special talent and the final two concerned beliefs that people with autism are dangerous. The findings from this study demonstrate that people with varying experience or knowledge of autism often hold inaccurate beliefs about autism. These findings improve our understandings of lay-beliefs about autism, and will aid the development and implementation of interventions designed to improve lay-knowledge of autism