Synthetic Analogues of the Snail Toxin 6-Bromo-2-mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels

Drugs do not act solely by canonical ligand–receptor binding interactions. Amphiphilic drugs partition into membranes, thereby perturbing bulk lipid bilayer properties and possibly altering the function of membrane proteins. Distinguishing membrane perturbation from more direct protein–ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogues. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogues and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Structure–activity relationships were determined for modulation of the Kv1.4 channel, bilayer partitioning, and bilayer perturbation. Neither membrane partitioning nor bilayer perturbation correlates with K+ channel modulation. We conclude that BrMT’s membrane interactions are not critical for its inhibition of Kv1.4 activation. Further, we found that alkyl or ether linkages can replace the chemically labile disulfide bond in the BrMT pharmacophore, and we identified additional regions of the scaffold that are amenable to chemical modification. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported

Signaling from β1- and β2-adrenergic receptors is defined by differential interactions with PDE4

β1- and β2-adrenergic receptors (βARs) are highly homologous, yet they play clearly distinct roles in cardiac physiology and pathology. Myocyte contraction, for instance, is readily stimulated by β1AR but not β2AR signaling, and chronic stimulation of the two receptors has opposing effects on myocyte apoptosis and cell survival. Differences in the assembly of macromolecular signaling complexes may explain the distinct biological outcomes. Here, we demonstrate that β1AR forms a signaling complex with a cAMP-specific phosphodiesterase (PDE) in a manner inherently different from a β2AR/β-arrestin/PDE complex reported previously. The β1AR binds a PDE variant, PDE4D8, in a direct manner, and occupancy of the receptor by an agonist causes dissociation of this complex. Conversely, agonist binding to the β2AR is a prerequisite for the recruitment of a complex consisting of β-arrestin and the PDE4D variant, PDE4D5, to the receptor. We propose that the distinct modes of interaction with PDEs result in divergent cAMP signals in the vicinity of the two receptors, thus, providing an additional layer of complexity to enforce the specificity of β1- and β2-adrenoceptor signaling

Rare coding variants in ten genes confer substantial risk for schizophrenia

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, PPeer reviewe

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

peer reviewe

Measuring Bahamian Lionfish Impacts to Marine Ecological Services Using Habitat Equivalency Analysis

Marine ecological services provide goods, amenities, food resources, and economic benefits to millions of people globally. The loss of these services, attributed to the infiltration of marine invasive species such as the Indo-Pacific lionfish (Pterois volitans/miles), is measurable. The highly successful lionfish now flourishes in great densities in the US Gulf of Mexico and Atlantic waters and the entire Caribbean, yet the loss of ecological services attributed to the invader has not yet been assessed. In this study, we employ a derivative of a well-utilized method of ecosystem valuation known as habitat equivalency analysis to measure the time-value-adjusted loss of biomass- and recruitment-related ecosystem services brought by lionfish to Bahamian reefs. Drawing upon the literature examples of tangible lionfish damages in the Bahamas, we (1) quantitatively evaluate the loss of ecosystem services instigated by lionfish by measuring the total service-year losses partitioned over yearly time steps, (2) provide a metric by which ocean managers may value the remunerations of Bahamian lionfish controls when weighed against removal costs, and (3) deliver a tool to quantify changes in ecosystem services as a consequence of invasive species impacts and control. We found that the invader imposed losses of 26.67 and 21.67 years to recruitment and biomass services per km2 of Bahamian reef if left uncontrolled. In the same accord, the most conservative Bahamian lionfish removal regime modeled, i.e., which produced a 50 % recovery of pre-lionfish ecosystem function over 10 years, provided service gains of 9.57 and 4.78 years per km2. These data deliver a platform upon which to quantify present and future fiscal costs of the lionfish invasion and also to value lionfish control efforts

Forecasting the Success of Invasive Marine Species; Lessons Learned from Purposeful Reef Fish Releases in the Hawaiian Islands

Eleven grouper, snapper, and emperor fish species were intentionally released in the Hawaiian Islands spanning the years 1955–1961 to produce new fisheries. Within 15 years, three of the introduced species established self-sustaining populations and eight did not. Two species, Lutjanus kasmira and Cephalopholis argus, are now considered invasive. We report on the results of a biophysical computer model which combines the life history traits of the inductees with prevailing oceanographic conditions in the Hawaiian Islands to hindcast the fate of the introduced fish. This comparative study is valuable in providing numeric insight into the characteristics that predispose fish introduced outside their native range to becoming invasive. Simulations created by the model spanning the years 1955–1970 succeeded to reproduce the establishment of the three species now found in the Hawaiian Islands and also replicated the failure of those fish that did not establish. Our results suggest that mortality rate, tolerance to water depth, age to maturity, and the quantity of individuals released are the best predictors of the establishment of the introduced fish in the Hawaiian Islands

Panel I: Gun-Related Crime and Enforcement: State and National Considerations

PANEL I : GUN-RELATED CRIME AND ENFORCEMENT: STATE AND NATIONAL CONSIDERATIONS Morgan Cloud, Charles Howard Candler Professor of Law, Emory University School of Law (Moderator) W. Matthew Dodge, Appellate Attorney at Federal Defender Program for the Northern District of Georgia Paul L. Howard, Jr., District Attorney, Fulton County David E. Patton, Executive Director and Attorney-in-Chief, Federal Defenders of New York Sally Yates, Partner, King & Spalding, and Former United States Deputy Attorney Genera

Panel I: Gun-Related Crime and Enforcement: State and National Considerations

PANEL I : GUN-RELATED CRIME AND ENFORCEMENT: STATE AND NATIONAL CONSIDERATIONS Morgan Cloud, Charles Howard Candler Professor of Law, Emory University School of Law (Moderator) W. Matthew Dodge, Appellate Attorney at Federal Defender Program for the Northern District of Georgia Paul L. Howard, Jr., District Attorney, Fulton County David E. Patton, Executive Director and Attorney-in-Chief, Federal Defenders of New York Sally Yates, Partner, King & Spalding, and Former United States Deputy Attorney Genera

An Update of the Visual_HEA Software to Improve the Implementation of the Habitat Equivalency Analysis Method

The Visual_HEA software tool was created in 2006 to facilitate the assessment of losses and gains in ecosystem services related to compensatory mitigation under the United States National Resource Damage Assessment Act (NRDA). Habitat Equivalency Analysis (HEA) is an ecological equivalence assessment method under NRDA that can be performed using the Visual_HEA software and for which it was named. The newers version – 2.6 – was recently enhanced and tested over several years to be adapted to the European context and to facilitate adherence to the Environmental Liability Directive (2004/35/EC) to compensate for environmental damages. Herein, enhancements, limitations, and a turnkey method of calculating variable gain and loss rates over space and time using the 2.6 version of the software are discussed. Major functionality enhancements include a quarterly discount calculation, increased decimal precision, gain calculations that extend into perpetuity, and the elimination of many small software “bugs”. A case study about the accidental pollution of the Mimizan River from a sodium hypochlorite spill at a paper mill illustrates the new functionalities of the software. The use of the HEA method to assess ecosystem services related to biodiversity offset has been widespread thanks to the development of this user-friendly software package. Furthermore, the HEA method implemented in Visual HEA_2.6 is recommended by the European Commission to enforce its Environmental Liability Directive and to size mitigations after accidental environmental damages