Fisheries dataset on moulting patterns and shell quality of American lobsters H. americanus in Atlantic Canada.

Monitoring the moulting phenology of American lobsters (Homarus americanus) is important for maintaining sustainable lobster stocks. Changes in lobster landings can affect reproduction and disease susceptibility. Data on lobster moult indicators and on life-history traits (sex, size) were collated from a twelve-year monitoring program (2004-2015) in six lobster fishing areas in Atlantic Canada. A total of 141,659 lobsters were sampled over 1,195 sampling events using a standardized protocol and commercial lobster fishing traps. The dataset contains pleopod stages, estimated hemolymph protein levels (°Brix values) and shell hardness as well as lobster sex and size. Evaluation of sex ratio dynamics is also possible but existing biases in sampling males and females needs to be noted. This dataset is valuable in terms of inferring spatio-temporal trends in the life history of lobsters, as well as in the analysis of their moult cycle, and hence more generally for fisheries science and marine ecology.

Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4.

Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 (43), and a backup clinical candidate, BMS-986141 (49). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.

Discovery of Potent Protease-Activated Receptor 4 Antagonists with in Vivo Antithrombotic Efficacy.

In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.

Identification of Polo-like kinase 1 interaction inhibitors using a novel cell-based assay.

Polo-like kinase 1 (Plk1) plays several roles in cell division and it is a recognized cancer drug target. Plk1 levels are elevated in cancer and several types of cancer cells are hypersensitive to Plk1 inhibition. Small molecule inhibitors of the kinase domain (KD) of Plk1 have been developed. Their selectivity is limited, which likely contributes to their toxicity. Polo-like kinases are characterized by a Polo-Box Domain (PBD), which mediates interactions with phosphorylation substrates or regulators. Inhibition of the PBD could allow better selectivity or result in different effects than inhibition of the KD. In vitro screens have been used to identify PBD inhibitors with mixed results. We developed the first cell-based assay to screen for PBD inhibitors, using Bioluminescence Resonance Energy Transfer (BRET). We screened through 112 983 compounds and characterized hits in secondary biochemical and biological assays. Subsequent Structure-Activity Relationship (SAR) analysis on our most promising hit revealed that it requires an alkylating function for its activity. In addition, we show that the previously reported PBD inhibitors thymoquinone and Poloxin are also alkylating agents. Our cell-based assay is a promising tool for the identification of new PBD inhibitors with more drug-like profiles using larger and more diverse chemical libraries.

The low friction contradiction (low friction or fiction).

Low friction is on everyone' lips, from companies to lecturers, some are just whispering and others are shouting the advantages of low friction self-ligating brackets. The low friction appliances get tremendous attention and publicity. Most major companies have a bracket that they describe as low fiction. Many clinicians have switched or are considering the switch to these brackets. Most companies present their low friction line describing and promoting their bracket design. In our opinion low friction is not only a question of bracket design. Low friction must be looked at, promoted and used as a complete philosophy. To insure maximum results the low friction clinicians will have to choose and respect the philosophy of the system. Using only a so-called low friction bracket will not assure the clinician the performance of low friction mechanics. This article will try to expose a low friction philosophy which goes beyond the bracket design. We will describe a global approach to low friction philosophy using the Damon System as an example. We do not imply that the Damon System is the only system that can get excellent results but it is a system that has a good track record and that has been on the market for many years.

Lysine sulfonamides as novel HIV-protease inhibitors: Nepsilon-acyl aromatic alpha-amino acids.

A series of lysine sulfonamide analogues bearing Nepsilon-acyl aromatic amino acids were synthesized using an efficient synthetic route. Evaluation of these novel protease inhibitors revealed compounds with high potency against wild-type and multiple-protease inhibitor-resistant HIV viruses.

Synthesis and structure--activity relationship of novel aminotetralin derivatives with high micro selective opioid affinity.

Several novel racemic aminotetralin derivatives have been prepared using a stereoselective aziridine ring opening reactions and were evaluated for their micro-opioid receptor binding affinity. Selectivity index towards other opioid receptors and antinociceptive activity in mice have been evaluated for the most potent derivatives.

Total Synthesis of Cryptophycins and Their 16-(3-Phenylacryloyl) Derivatives.

Cryptophycin A, a cyclic depsipeptide isolated from the blue-green alga (cyanobacterium) Nostocsp.GSV 224, has shown excellent activity against solid tumors implanted in mice. The benzylic epoxide, which was shown to be very important for biological activity, is also fairly unstable under both acidic and alkaline conditions. The high doses needed to observe in vivo activity might be a result of this instability. In order to solve this problem while preserving the electrophilic character of the benzylic position, enones 1 and 2 have been proposed as promising analogs of the natural product, and a convergent total synthesis of these compounds is described. In addition, the same strategy was used to prepare Cryptophycins A, B, C, and D.