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PubMed2026

Development of a multi-copy integration platform in Kluyveromyces marxianus enabled by a computational method for genome-wide identification of multi-copy integration loci.

Multi-copy integration is a core strategy for redirecting metabolic flux toward target compounds. However, its application has been hampered by the absence of methods for systematically identifying native multi-copy genomic loci. To overcome this, we developed a computational procedure for genome-wide identification of such loci. Theoretically, this method is potentially applicable to any genome-sequenced species as it only requires the genomic assembly of the target species as input. Applying the procedure to Kluyveromyces marxianus, we identified four groups of loci (KmCS1-4). Combining these loci-KmCS1-4 and the traditional 26S rDNA-with 14 markers with graded selection strengths, we established a versatile multi-copy integration toolkit comprising 70 plasmids. Each plasmid exhibits a unique integration pattern, collectively forming an integration profile. This profile serves as a manual, enabling users to select appropriate tools tailored to the expression requirements of rate-limiting enzymes in their pathways. Applying representative plasmids exhibiting low-, medium-, and high-copy integration patterns to lycopene biosynthesis modules resulted in lycopene titers of 3.5, 6.8 and 40.5 mg/L, corresponding to 2, 6 and 9 genomic copies, respectively, demonstrating a positive correlation between lycopene titers, genomic copy numbers and integration patterns, which highlights the versatility of the toolkit and its supporting manual. Our study not only provides a broadly applicable methodology for genome-wide identification of multi-copy loci, but also an efficient integration platform for K. marxianus.

Kluyveromyces marxianus↗
PubMed1988

A versatile computational method for the determination of areas under the curve and moment curve following multidose drug administration.

The accurate determination of area under the biologic fluid concentration-time curve (AUC) and area under the first moment curve (AUMC) are important in the calculation of a compound's pharmacokinetic parameter estimates. Although numerous mathematical methods exist for the calculation of both AUC and AUMC under varying conditions, some permit direct computation of areas, whereas others only approximate the true areas. In this study, we describe an alternative mathematical method which allows the direct calculation of either the AUC or AUMC after any dose of drug administered by any route. Simulated data with known areas were used to assess the accuracy of the proposed method and compared to area calculations obtained from widely used published methods. Experiments were also performed under conditions of varying elimination half-lives and reduced numbers of concentration-time values. Under any experimental condition, the newly proposed method was the most accurate in determining both the AUC and AUMC. Percent deviations from exact area values were less than or equal to 0.11% with the proposed method, whereas as much as 30% deviation was observed using other methods of calculation. These findings support the accuracy of the proposed method in calculating the AUC or AUMC and its utility in data analysis.

Infusions, Intravenous↗
PubMed1992

Computer methods in child language research: four principles for the use of archived data.

With the increasing use of computers in language research, there is a need for caution concerning several new issues of data accountability. This paper presents four principles for archive-based language research: Maximum Readability and Minimum Bias; Consistent Encoding for exhaustive computer search; Systematic Contrastiveness; and Data Comparability in elicitation, transcription and coding. These and related principles are illustrated by examples from existing computer archives, and strategies are suggested for minimizing detrimental effects of violations. Finally, the paper describes some implications of the principles for properties of a field-wide and international standard of transcription of language data.

Archives↗
PubMed1991

Computational method for the design of enzymes with altered substrate specificity.

A combination of enzyme kinetics and X-ray crystallographic analysis of site-specific mutants has been used to probe the determinants of substrate specificity for the enzyme alpha-lytic protease. We now present a generalized model for understanding the effects of mutagenesis on enzyme substrate specificity. This algorithm uses a library of side-chain rotamers to sample conformation space within the binding site for the enzyme-substrate complex. The free energy of each conformation is evaluated with a standard molecular mechanics force field, modified to include a solvation energy term. This rapid energy calculation based on coarse conformation sampling quite accurately predicts the relative catalytic efficiency of over 40 different alpha-lytic protease-substrate combinations. Unlike other computational approaches, with this method it is feasible to evaluate all possible mutations within the binding site. Using this algorithm, we have successfully designed a protease that is both highly active and selective for a non-natural substrate. These encouraging results indicate that it is possible to design altered enzymes solely on the basis of empirical energy calculations.

Algorithms↗
PubMed1989

A least-squares computer method for the determination of the molecular ratio of conjugates between two different proteins from the results of the amino acid analysis.

A method for the determination of the composition of a conjugate between two different proteins by amino acid analysis followed by least-squares evaluation of the concentration ratio of the two components is presented. The method is based solely on calculations and avoids the use of labeled residues. A computer program, written in BASIC, is also presented to perform the calculations.

Amino Acids↗