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AbstractIn this article we present a dynamic modeling framework, which facilitates an evaluation of a breakthrough innovation. One of the powerful aspects of this framework is its robustness. This process helps identify directions that increase the probability for finding possible breakthrough ideas and eventually products. This framework facilitates the initial evaluation of individual projects and also has value in evaluating accepted projects as they progress. Lastly, this framework is instrumental in the critical “go, no-go” decision, which inevitably happens somewhere along the line for most revolutionary products.

We describe a new serine protease inhibition motif in which binding is mediated by a cluster of very short hydrogen bonds (<2.3 Å) at the active site. This protease-inhibitor binding paradigm is observed at high resolution in a large set of crystal structures of trypsin, thrombin, and urokinase-type plasminogen activator (uPA) bound with a series of small molecule inhibitors (2-(2-phenol)indoles and 2-(2-phenol)benzimidazoles). In each complex there are eight enzyme-inhibitor or enzyme-water-inhibitor hydrogen bonds at the active site, three of which are very short. These short hydrogen bonds connect a triangle of oxygen atoms comprising OSer195γ, a water molecule co-bound in the oxyanion hole (H2Ooxy), and the phenolate oxygen atom of the inhibitor (O6′). Two of the other hydrogen bonds between the inhibitor and active site of the trypsin and uPA complexes become short in the thrombin counterparts, extending the three-centered short hydrogen-bonding array into a tetrahedral array of atoms (three oxygen and one nitrogen) involved in short hydrogen bonds. In the uPA complexes, the extensive hydrogen-bonding interactions at the active site prevent the inhibitor S1 amidine from forming direct hydrogen bonds with Asp189 because the S1 site is deeper in uPA than in trypsin or thrombin.

Accommodation of divalent cations (M2+) and dimer cations ([MOM]2+) in zeolites requires the presence of two charge-exchange sites in close proximity to each other. Since each charge-exchange site is associated with a framework Al atom, this constraint requires that 2 Al atoms be located in next-nearest-neighbor T sites. The maximum number of divalent cations that can be accommodated by ZSM-5 as either Z-M2+Z−or Z−[MOM]2+Z−(where Z−represents a cation-exchange site in the zeolite) has been calculated for a given value of Si/Al, and the results are reported as the maximum value of M/Al. Two cases for the distribution of framework Al atoms are considered: random placement in T sites and placement governed by equilibrium thermodynamics. For both M2+and [MOM]2+the maximum value of M/Al is significantly less than 0.5 and 1.0, respectively, because of the required constraints on the Al–Al pairs, and decreases as the Si/Al ratio increases. For M2+cations the distribution of specific cations (Co2+, Cu2+, Fe2+, Ni2+, Pd2+, Pt2+, and Zn2+) was determined using energies predicted from electronic structure calculations. M2+cations are preferentially situated in rings containing either five or six T atoms. The manner in which the Al atoms are distributed among T sites affects the distribution of M2+cations among different types of rings.

The distribution of framework Al in ZSM-5 was simulated for various Si/Al ratios and the results used to determine the fraction of Al atoms in next nearest neighbors (NNN) T sites. All the 4-, 5-, and 6-membered rings were identified in the unit cell and the fraction of these rings with 0, 1, 2, and 3 Al was calculated. Lastly, the radial distribution function of Al–Al pairs, the number of Al's expected within a sphere of radius, r, centered around an Al (E), and the probability of finding at least one Al within a sphere of radius, r, centered around an Al (P) were calculated for different Si/Al ratios. Based on these results, the probability of locating NNN pairs of Al atoms situated at a distance suitable for the stabilization of M2+and [M–O–M]2+cations were carried out and then used to determine maximum values for M2+/Al and [M–O–M]2+/Al. The value of M2+/Al is 0.12 for Si/Al=12 and 0.07 for Si/Al=24, and the value of [M–O–M]2+is 0.30 for Si/Al=12 and 0.19 for Si/Al=24. The values of M2+/Al obtained theoretically are in reasonable agreement with those observed experimentally for Pd–ZSM-5. A significant finding of our simulation is that Löwenstein's rule is the dominant factor governing short-range correlations of framework Al atoms, and hence the distribution of NNN pairs of Al atoms. As a consequence, analytical theories that include consideration of Löwenstein's rule provide rather accurate estimates of the probability of finding Al NNN pairs.

Dog kidneys were perfused with a newly developed perfusate containing adenosine and PO4for 48 hr, stored in the same perfusate for an additional 24 hr without perfusion (total preservation time:72 hr), and transplanted with immediate contralateral nephrectomy. Posttransplant renal function and biochemical analysis of the kidneys revealed practically no additional preservation-induced damage during the cold storage period. Serum creatinine levels reached normal between the third and eighth day posttransplant. This preservation method may be the method of choice for patients receiving postoperative cyclosporine therapy—and, in addition, facilitate organ sharing between transplant centers, thus reducing wastage of cadaveric kidneys.

Published ahead of print September 20, 2016.

Published ahead of print June 1, 2016

Several letters to the editor in response to articles published in previous issues related to singers David Bowie, Ronnie Spector and rock group Savage Rose are presented.

To the Editor.—In a recent article entitled "Cost-effectiveness of Screening Women at Moderate Risk for Genital Infections Caused by Chlamydia trachomatis,"1 there appear to be two contradictory statements that are crucial to the conclusions made by the authors.At one point, the statement is made that "the absolute sensitivity of a single endocervical direct antigen test was assumed to be 53% (ie, a direct antigen test would detect a true infection 53% of the time), and the specificity, 96%."Later in the article, while discussing the strategy of performing this test on all patients and treating those with positive results, the authors state that, "if this strategy were implemented, only 53% of treated patients would actually be infected." And later in the same paragraph comes another confusing statement that is more in agreement with their first statement regarding the test's sensitivity: "only half of infected patients would be