Furfural inhibits growth by limiting sulfur assimilation in ethanologenic Escherichia coli strain LY180.

A wide variety of commercial products can be potentially made from monomeric sugars produced by the dilute acid hydrolysis of lignocellulosic biomass. However, this process is accompanied by side products such as furfural that hinder microbial growth and fermentation. To investigate the mechanism of furfural inhibition, mRNA microarrays of an ethanologenic strain of Escherichia coli (LY180) were compared immediately prior to and 15 min after a moderate furfural challenge. Expression of genes and regulators associated with the biosynthesis of cysteine and methionine was increased by furfural, consistent with a limitation of these critical metabolites. This was in contrast to a general stringent response and decreased expression of many other biosynthetic genes. Of the 20 amino acids individually tested as supplements (100 microM each), cysteine and methionine were the most effective in increasing furfural tolerance with serine (precursor of cysteine), histidine, and arginine of lesser benefit. Supplementation with other reduced sulfur sources such as d-cysteine and thiosulfate also increased furfural tolerance. In contrast, supplementation with taurine, a sulfur source that requires 3 molecules of NADPH for sulfur assimilation, was of no benefit. Furfural tolerance was also increased by inserting a plasmid encoding pntAB, a cytoplasmic NADH/NADPH transhydrogenase. Based on these results, a model is proposed for the inhibition of growth in which the reduction of furfural by YqhD, an enzyme with a low K(m) for NADPH, depletes NADPH sufficiently to limit the assimilation of sulfur into amino acids (cysteine and methionine) by CysIJ (sulfite reductase).

A family of ring system-based structural fragments for use in structure-activity studies: database mining and recursive partitioning.

In earlier work from our laboratory, we have described the use of the ring system and ring scaffold as descriptors. We showed that these descriptors could be used for fast compound clustering, novelty determination, compound acquisition, and combinatorial library design. Here we extend the concept to a whole family of structural descriptors with the ring system as the centerpiece. We show how this simple idea can be used to build powerful search tools for mining chemical databases in useful ways. We have also built recursive partition trees using these fragments as descriptors. We will discuss how these trees can help in analyzing complex structure-activity data.

Recurrence after complete cryoablation of colorectal liver metastases: analysis of prognostic features.

This study critically evaluated the prognostic determinants for disease-free survival (DFS) after cryoablation for colorectal liver metastases. An observational cohort study of prospectively collected data on 135 patients who underwent cryoablation with or without resection for colorectal liver metastases was performed. Univariate and multivariate analyses were used to determine the prognostic factors for overall DFS, cryosite DFS, remaining liver DFS, and extrahepatic DFS. Overall, 115 patients (85%) developed recurrence at the cryosite (44%), and the remaining patients developed recurrence at the liver (62%) and extrahepatic site (71%). In univariate analysis, preoperative and postoperative carcinoembryonic antigen (CEA) were significant for overall DFS. Distribution of metastases, operation type, total number of metastases, number of cryotreated metastases, largest size of cryotreated metastasis, and postoperative CEA were significant for cryosite DFS. The number of cryotreated metastases and postoperative CEA were significant for remaining liver DFS. The largest size of cryotreated metastasis, and preoperative and postoperative CEA were significant for extrahepatic DFS. In multivariate analysis, resection plus cryoablation, < or =7 liver metastases and < or =3 cm cryotreated metastasis were independently associated with an improved cryosite DFS. Preoperative CEA of < or =5 ng/mL was independently associated with an improved overall and extrahepatic DFS. The role of CEA in colorectal metastasis is important. Resection plus cryoablation rather than cryoablation alone should be used for larger lesions.

Anthranilate 4H-oxazol-5-ones: novel small molecule antibacterial acyl carrier protein synthase (AcpS) inhibitors.

D-optimal design and Projection to Latent Structures (PLS) analysis were used to optimize screening hit 5 (B. subtilis AcpS IC(50): 15 microM, B. subtilis MIC: >200 microM) into a series of 4H-oxazol-5-one, small molecule, antibacterial, AcpS inhibitors. Specifically, 15, 16 and 18 show microM or sub-microM AcpS inhibition (IC(50)s: 15: 1.1 microM, 16: 1.5 microM, 18: 0.27 microM) and moderate antibacterial activity (MICs: 12.5-50 microM) against B. subtilis, E. faecalis ATCC, E. faecalis VRE and S. pneumo+.

A fresh look at pharmaceutical screening library design.

Most current methods for the design of pharmaceutical screening libraries centre around compound diversity. We present arguments for a different approach, involving a fixed number of analogs around a set of medicinally relevant scaffolds. Most current approaches to screening library design emphasize wide coverage of chemical space at the expense of poor local representation. We propose constructing uniform libraries around fixed ring scaffolds with "adequate" representation so as not to miss potentially active series.

The other side of the coin.

I am writing in response to Sue Haworth's letter in the Nursing Standard (week ending December 5) with regards to reduced RCN membership fees for undergraduate student nurses.