This paper serves the twofold purpose of demonstrating a numerical technique that appears to have potential in studies of nonlinear reactive transport problems and of presenting a case study where the implications of reactive transport processes are profound. The case study relates to the Fuhrberger Feld aquifer in northern Germany, which provides the bulk of the water supply for the half‐million city of Hannover. Part of the aquifer receives a strong influx of nitrate from agricultural activities. The nitrate in the aquifer is microbially transformed into sulfate, the transformation depending on the availability of reduced sulfur compounds present in the sediment, and the sulfate is also transformed further. The individual transformations occur within distinct reaction zones in the aquifer. The relevant dynamic processes can be formulated as a nonlinear transport problem involving multiple interacting species in dissolved or solid form. The system is simulated using a finite element‐based technique that generates a symmetric coefficient matrix for the transport equation, while providing second‐order accuracy in time. The form of the matrix allows the use of a highly efficient and robust symmetric conjugate gradient solver. The technique provides an ample spatial resolution capacity at reasonable cost and handles grids with irregular geometry in two or three dimensions. The convenience and versatility of conventional finite elements is retained. A vertical‐section simulation identifies different reaction zones in the aquifer and gives insight into the effect of the controlling parameters. The simulation study is a first step in the development of a prognosis for the fate of the groundwater resource.

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Rod-Like Dispiro(5.1.5.2) Compounds.-Starting with the dispiro(5.1.5.2)trione (I), a number of sym. and unsym. substituted spiro compounds are synthesized such as is demonstrated for some examples. The formation of the trans-trans isomers of (II), its dicyano analogue, its dibutoxy derivative as well as its diester, e.g. (V), are favored. Some of the compounds functionalized with flexible side groups show narrow liquid-crystal phases. -(BOETTCHER, J.; HARTMANN, R.; VOEGTLE, F.; Chem.

Target 2035, an international federation of biomedical scientists from the public and private sectors, is leveraging ‘open’ principles to develop a pharmacological tool for every human protein.

<div>Abstract<p><i>KRAS</i> is the most frequently mutated driver of pancreatic, colorectal, and non–small cell lung cancers. Direct KRAS blockade has proved challenging, and inhibition of a key downstream effector pathway, the RAF–MEK–ERK cascade, has shown limited success because of activation of feedback networks that keep the pathway in check. We hypothesized that inhibiting SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. We report the discovery of a highly potent, selective, and orally bioavailable small-molecule SOS1 inhibitor, BI-3406, that binds to the catalytic domain of SOS1, thereby preventing the interaction with KRAS. BI-3406 reduces formation of GTP-loaded RAS and limits cellular proliferation of a broad range of KRAS-driven cancers. Importantly, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances sensitivity of KRAS-dependent cancers to MEK inhibition. Combined SOS1 and MEK inhibition represents a novel and effective therapeutic concept to address KRAS-driven tumors.</p>Significance:<p>To date, there are no effective targeted pan-KRAS therapies. In-depth characterization of BI-3406 activity and identification of MEK inhibitors as effective combination partners provide an attractive therapeutic concept for the majority of KRAS-mutant cancers, including those fueled by the most prevalent mutant KRAS oncoproteins, G12D, G12V, G12C, and G13D.</p><p><i>See related commentary by Zhao et al., p. 17</i>.</p><p><i>This article is highlighted in the In This Issue feature, p. 1</i></p></div>