Utah’s Watershed Restoration Initiative: Restoring Watersheds at a Landscape Scale

Abstract: The Utah Watershed Restoration Initiative (WRI) is a partnership-based program, administered by the Utah Department of Natural Resources, which seeks to improve the functional capacity of high priority watersheds throughout the state. Since its inception in 2006, the WRI partnership has completed nearly 1,500 projects to restore and rehabilitate over 526,091 ha in Utah watersheds. The WRI program is unique to the west, in that it transcends jurisdictional boundaries, and local, state, and federal management authority to focus finite resources on completing high priority conservation projects. We surveyed selected WRI selected participants in 2015 to determine what factors they believed most contributed to the overall success of the program. Survey respondents attributed the success of the WRI program to: 1) engaged leadership at multiple levels, 2) a bottom-up hierarchy, 3) a history of collaboration, 4) practice partnerships, 5) a science-based approach, 6) operating at a meaningful spatial scale, 7) being solution minded, not problem focused, and 8) unselfish sharing of resources. In this paper we discuss these success factors and provide recommendations to those desiring to implement voluntary incentive-based landscape conservation strategies

Structure-Guided Optimization of Replication Protein A (RPA)–DNA Interaction Inhibitors

Replication protein A (RPA) is the major human single stranded DNA (ssDNA)-binding protein, playing essential roles in DNA replication, repair, recombination, and DNA-damage response (DDR). Inhibition of RPA–DNA interactions represents a therapeutic strategy for cancer drug discovery and has great potential to provide single agent anticancer activity and to synergize with both common DNA damaging chemotherapeutics and newer targeted anticancer agents. In this letter, a new series of analogues based on our previously reported TDRL-551 (4) compound were designed to improve potency and physicochemical properties. Molecular docking studies guided molecular insights, and further SAR exploration led to the identification of a series of novel compounds with low micromolar RPA inhibitory activity, increased solubility, and excellent cellular up-take. Among a series of analogues, compounds 43, 44, 45, and 46 hold promise for further development of novel anticancer agents

Point-of-care testing for disasters: needs assessment, strategic planning, and future design.

Objective evidence-based national surveys serve as a first step in identifying suitable point-of-care device designs, effective test clusters, and environmental operating conditions. Preliminary survey results show the need for point-of-care testing (POCT) devices using test clusters that specifically detect pathogens found in disaster scenarios. Hurricane Katrina, the tsunami in southeast Asia, and the current influenza pandemic (H1N1, "swine flu") vividly illustrate lack of national and global preparedness. Gap analysis of current POCT devices versus survey results reveals how POCT needs can be fulfilled. Future thinking will help avoid the worst consequences of disasters on the horizon, such as extensively drug-resistant tuberculosis and pandemic influenzas. A global effort must be made to improve POC technologies to rapidly diagnose and treat patients to improve triaging, on-site decision making, and, ultimately, economic and medical outcomes

Design and Structure-Guided Development of Novel Inhibitors of the Xeroderma Pigmentosum Group A (XPA) Protein–DNA Interaction

XPA is a unique and essential protein required for the nucleotide excision DNA repair pathway and represents a therapeutic target in oncology. Herein, we are the first to develop novel inhibitors of the XPA–DNA interaction through structure-guided drug design efforts. Ester derivatives of the compounds 1 (X80), 22, and 24 displayed excellent inhibitory activity (IC50 of 0.82 ± 0.18 μM and 1.3 ± 0.22 μM, respectively) but poor solubility. We have synthesized novel amide derivatives that retain potency and have much improved solubility. Furthermore, compound 1 analogs exhibited good specificity for XPA over RPA (replication protein A), another DNA-binding protein that participates in the nucleotide excision repair (NER) pathway. Importantly, there were no significant interactions observed by the X80 class of compounds directly with DNA. Molecular docking studies revealed a mechanistic model for the interaction, and these studies could serve as the basis for continued analysis of structure–activity relationships and drug development efforts of this novel target

Illusory Percepts from Auditory Adaptation

Phenomena resembling tinnitus and Zwicker phantom tone are seen to result from an auditory gain adaptation mechanism that attempts to make full use of a fixed-capacity channel. In the case of tinnitus, the gain adaptation enhances internal noise of a frequency band otherwise silent due to damage. This generates a percept of a phantom sound as a consequence of hearing loss. In the case of Zwicker tone, a frequency band is temporarily silent during the presentation of a notched broad-band sound, resulting in a percept of a tone at the notched frequency. The model suggests a link between tinnitus and the Zwicker tone percept, in that it predicts different results for normal and tinnitus subjects due to a loss of instantaneous nonlinear compression. Listening experiments on 44 subjects show that tinnitus subjects (11 of 44) are significantly more likely to hear the Zwicker tone. This psychoacoustic experiment establishes the first empirical link between the Zwicker tone percept and tinnitus. Together with the modeling results, this supports the hypothesis that the phantom percept is a consequence of a central adaptation mechanism confronted with a degraded sensory apparatus

The New Horizons Spacecraft

The New Horizons spacecraft was launched on 19 January 2006. The spacecraft was designed to provide a platform for seven instruments that will collect and return data from Pluto in 2015. The design drew on heritage from previous missions developed at The Johns Hopkins University Applied Physics Laboratory (APL) and other missions such as Ulysses. The trajectory design imposed constraints on mass and structural strength to meet the high launch acceleration needed to reach the Pluto system prior to the year 2020. The spacecraft subsystems were designed to meet tight mass and power allocations, yet provide the necessary control and data handling finesse to support data collection and return when the one-way light time during the Pluto flyby is 4.5 hours. Missions to the outer solar system require a radioisotope thermoelectric generator (RTG) to supply electrical power, and a single RTG is used by New Horizons. To accommodate this constraint, the spacecraft electronics were designed to operate on less than 200 W. The spacecraft system architecture provides sufficient redundancy to provide a probability of mission success of greater than 0.85, even with a mission duration of over 10 years. The spacecraft is now on its way to Pluto, with an arrival date of 14 July 2015. Initial inflight tests have verified that the spacecraft will meet the design requirements.Comment: 33 pages, 13 figures, 4 tables; To appear in a special volume of Space Science Reviews on the New Horizons missio

Discovery and development of novel DNA-PK inhibitors by targeting the unique Ku–DNA interaction

DNA-dependent protein kinase (DNA-PK) plays a critical role in the non-homologous end joining (NHEJ) repair pathway and the DNA damage response (DDR). DNA-PK has therefore been pursued for the development of anti-cancer therapeutics in combination with ionizing radiation (IR). We report the discovery of a new class of DNA-PK inhibitors that act via a novel mechanism of action, inhibition of the Ku-DNA interaction. We have developed a series of highly potent and specific Ku-DNA binding inhibitors (Ku-DBi's) that block the Ku-DNA interaction and inhibit DNA-PK kinase activity. Ku-DBi's directly interact with the Ku and inhibit in vitro NHEJ, cellular NHEJ, and potentiate the cellular activity of radiomimetic agents and IR. Analysis of Ku-null cells demonstrates that Ku-DBi's cellular activity is a direct result of Ku inhibition, as Ku-null cells are insensitive to Ku-DBi's. The utility of Ku-DBi's was also revealed in a CRISPR gene-editing model where we demonstrate that the efficiency of gene insertion events was increased in cells pre-treated with Ku-DBi's, consistent with inhibition of NHEJ and activation of homologous recombination to facilitate gene insertion. These data demonstrate the discovery and application of new series of compounds that modulate DNA repair pathways via a unique mechanism of action