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PubMed2003

Optimization of experimental design in fMRI: a general framework using a genetic algorithm.

This article describes a method for selecting design parameters and a particular sequence of events in fMRI so as to maximize statistical power and psychological validity. Our approach uses a genetic algorithm (GA), a class of flexible search algorithms that optimize designs with respect to single or multiple measures of fitness. Two strengths of the GA framework are that (1) it operates with any sort of model, allowing for very specific parameterization of experimental conditions, including nonstandard trial types and experimentally observed scanner autocorrelation, and (2) it is flexible with respect to fitness criteria, allowing optimization over known or novel fitness measures. We describe how genetic algorithms may be applied to experimental design for fMRI, and we use the framework to explore the space of possible fMRI design parameters, with the goal of providing information about optimal design choices for several types of designs. In our simulations, we considered three fitness measures: contrast estimation efficiency, hemodynamic response estimation efficiency, and design counterbalancing. Although there are inherent trade-offs between these three fitness measures, GA optimization can produce designs that outperform random designs on all three criteria simultaneously.

Algorithms↗

PubMedDate not supplied

Assessment of the optimal atrioventricular delay in dual chamber-paced patients by a portable scintillation probe (VEST).

BACKGROUND: The optimal atrioventricular delay in dual-chamber pacing differs from patient to patient. The availability of a portable scintillation probe (VEST) enables noninvasive monitoring of left ventricular function. METHODS AND RESULTS: Hemodynamic variations were measured in 10 patients with programmable DDD pacemakers. The ejection fraction, stroke volume, and diastolic and systolic volume were evaluated, programming six different atrioventricular delays ranging from 75 to 200 msec, to determine the most favorable atrioventricular delay. Comparing left ventricular ejection fraction (LVEF), stroke volume, and end-diastolic and end-systolic volume at each DVI mode with a preceding DVI setting of 75 msec, all parameters at 200 msec were statistically different from those at 100 msec. An increase of LVEF and stroke volume and a decrease of end-systolic volume was found. In only five patients a switch of VVI mode to the optimal DVI mode results in an increase of LVEF of more than 5%. CONCLUSIONS: Our study stresses the importance of optimizing atrioventricular delay. The VEST system permits these measurements, increasing the accuracy of the determination of optimal atrioventricular delay, and appears to be valuable in the management of patients with cardiac dual-chamber pacemakers.

Aged↗

PubMedDate not supplied

Cardiac gated equilibrium radionuclide angiography and multiharmonic Fourier phase analysis: optimal acquisition parameters in arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Multiharmonic Fourier phase analysis of radionuclide angiography is a well-established method for the diagnosis of arrhythmogenic right ventricular cardiomyopathy. We sought to determine the optimal acquisition parameters: number of frames per cycle and number of counts per frame, with all other acquisition and processing parameters being fixed. METHODS AND RESULTS: Radionuclide angiography with list mode acquisition was performed in 10 normal subjects (pilot group) and 11 patients with arrhythmogenic right ventricular cardiomyopathy (validation group), allowing the reconstruction of electrocardiography-gated constant phase studies with different parameters: 16, 24, and 32 frames per cycle and 200, 400, 600, and 800 kcounts per frame. Three harmonics Fourier phase analysis was applied, and optimal acquisition parameters (defined as those providing best homogeneous phase distribution histogram in the pilot group) were defined as judged by the H3 right ventricular phase SD and delta 95%. These were 16 frames per cycle and 600 kcounts per frame. Then we verified in the validation group that these optimal acquisition parameters did not induce any significant relative loss of information compared with other acquisition parameters with more temporal resolution (24 and 32 frames per cycle) or more statistics (800 kcounts per frame). This result was realized by the calculation of normalized H3 right ventricular SD, right ventricular delta 95%, and (SD[left ventricle] - SD[right ventricle]). CONCLUSIONS: In practice, 16 frames per cycle and 600 kcounts per frame are optimal for multiharmonic Fourier phase analysis, with all other acquisition and processing variables being fixed as specified.

Adult↗

PubMed2002

Optimization of the MHC class I peptide cargo is dependent on tapasin.

The loading of MHC class I molecules with their peptide cargo is undertaken by a multimolecular peptide loading complex within the endoplasmic reticulum. We show that MHC class I molecules can optimize their peptide repertoire over time and that this process is dependent on tapasin. Optimization of the peptide repertoire is both quantitatively and qualitatively improved by tapasin. The extent of optimization is maximal when MHC class I molecules are allowed to load within the fully assembled peptide loading complex. Finally, we identify a single natural polymorphism (116D>Y) in HLA-B*4402 that permits tapasin-independent loading of HLA-B*4405 (116Y). In the presence of tapasin, the tapasin-independent allele B*4405 (116Y) acquires a repertoire of peptides that is less optimal than the tapasin-dependent allele B*4402 (116D).

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

Optimizing parameters for computer-aided diagnosis of microcalcifications at mammography.

RATIONALE AND OBJECTIVES: The purpose of this study was to optimize selection of the mammographic features most useful in discriminating benign from malignant clustered microcalcifications. MATERIALS AND METHODS: The computer-aided diagnosis (CAD) system automatically extracted from digitized mammograms 13 quantitative features characterizing microcalcification clusters. Archival cases (n = 134; patient age range, 31-77 years; mean age, 56.8 years) with known histopathologic results (79 malignant, 55 benign) were selected. Three radiologists at three facilities independently analyzed the microcalcifications by using the CAD system. Stepwise discriminant analysis selected the features best discriminating benign from malignant microcalcifications. A classification scheme was constructed on the basis of these optimized features, and its performance was evaluated by using receiver operating characteristic (ROC) analysis. RESULTS: Six of the 13 variables extracted by the CAD system were selected by stepwise determinant analysis for generating the classification scheme, which yielded an ROC curve with an area (Az) of 0.98, specificity of 83.64%, positive predictive value of 89.53%, and accuracy of 91.79% for 98% sensitivity. When patient age was an additional variable, the scheme's performance improved, but this was not statistically significant (Az = 0.98). The ROC curve of the classifier (without age as an additional variable) yielded a high Az of 0.96 for patients younger than 50 years and an even higher (P < .02) Az of 0.99 for those 50 years or older. CONCLUSION: Stepwise discriminant analysis optimized performance of a classification scheme for microcalcifications by selecting six optimized features. Scheme performance was significantly (P < .02) higher for women 50 years or older, but the addition of patient age as a variable did not produce a statistically significant increase in performance.

Adult↗

PubMed2001

Optimal electrocardiographically triggered phase for reducing motion artifact at electron-beam CT in the coronary artery.

RATIONALE AND OBJECTIVES: The authors performed this study to (a) investigate coronary movement with electron-beam computed tomography (CT) and (b) find the optimal electrocardiographic (ECG) triggering phase for eliminating motion artifact. MATERIALS AND METHODS: One hundred fifty-one patients without arrhythmia were examined with electron-beam CT. First, movie scans were obtained to create displacement and velocity graphs of coronary artery movement. Then, a volume scan with an exposure time of 100 msec was obtained with various ECG trigger settings. RESULTS: Movement patterns of coronary arteries varied with heart rate. Optimal triggering phase was before atrial systole (near 71% of the R-R interval) when heart rate was slower than 68 beats per minute and at ventricular end systole when heart rate was fast. Rate of severe motion artifacts decreased from 43% to 0% when triggering was altered from 80% of the R-R interval to the individual optimal value. Experimental values of the optimal phase at different heart rates were derived, and severe motion artifact was only 3.0% with these values. CONCLUSION: ECG triggering set according to the heart rate enables a great reduction in motion artifacts at electron-beam CT with a 100-msec exposure time. The results may have implications for magnetic resonance imaging of the coronary artery.

Adult↗

PubMed2003

Application of optimal control theory to the design of broadband excitation pulses for high-resolution NMR.

Optimal control theory is considered as a methodology for pulse sequence design in NMR. It provides the flexibility for systematically imposing desirable constraints on spin system evolution and therefore has a wealth of applications. We have chosen an elementary example to illustrate the capabilities of the optimal control formalism: broadband, constant phase excitation which tolerates miscalibration of RF power and variations in RF homogeneity relevant for standard high-resolution probes. The chosen design criteria were transformation of I(z)-->I(x) over resonance offsets of +/- 20 kHz and RF variability of +/-5%, with a pulse length of 2 ms. Simulations of the resulting pulse transform I(z)-->0.995I(x) over the target ranges in resonance offset and RF variability. Acceptably uniform excitation is obtained over a much larger range of RF variability (approximately 45%) than the strict design limits. The pulse performs well in simulations that include homonuclear and heteronuclear J-couplings. Experimental spectra obtained from 100% 13C-labeled lysine show only minimal coupling effects, in excellent agreement with the simulations. By increasing pulse power and reducing pulse length, we demonstrate experimental excitation of 1H over +/-32 kHz, with phase variations in the spectra <8 degrees and peak amplitudes >93% of maximum. Further improvements in broadband excitation by optimized pulses (BEBOP) may be possible by applying more sophisticated implementations of the optimal control formalism.

Algorithms↗

PubMedDate not supplied

[Progress in optimizing dosimetry plans in stereotactic radiotherapy in the Salt Group (Saint-Anne-Lariboisière-Tenon].

We began intracranial stereotactic irradiation under the direction of O Betti 11 years ago. At the present time, we believe it is interesting to present the methodologies of the SALT (Saint-Anne-Lariboisière-Tenon) group. Up to the present time we have irradiated 693 patients using a single fraction. Arteriovenous malformations (AVMs) represented the majority (90%) of treated lesions. Irradiation protocol has little changed since 1986, and the localization of the target volume was performed in the neurosurgery department of St Anne Hospital, France. The stereotactic images (computerized tomography [CT], angiography) were sent to the radiotherapy department of Tenon Hospital through the French public digital network NUMERIS. Protocol was realized using the stereotactic ARTEMIS-3D/Dosigray TPS. The lesion volume was filled by one or more spherical or elliptical subvolumes using the "Associated Target Methodology". The interactive adjustment of subvolumes was based on the 3D graphical representations of the lesion. The direct optimization of the irradiation space was performed by managing parameters provided by the DDB (Dosimetric Data Base) such as the number of arcs, their angular position, as well as the starting and the ending point of each arc. The evaluation of the calculated dose distribution was made using quantitative parameters. The second method of optimization was based on the minibeam intensity modulation using a mathematical theory of inverse problems and singular value decomposition (SVD) analysis. At the present time, due to technical reasons, linear accelerators do not permit the modulation of intensity of arctherapy. Thus we transformed the profiles of irregular forms into rectangular profiles of modulated ponderation, with each optimized plan being evaluated before its implementation. The criteria of evaluation were derived from the differential and cumulative dose volume histograms (DVH). The DVHs permitted the evaluation of the volumes of underdosage and overdosage inside the lesion and in the healthy tissue, respectively. Using DVHs, we have defined parameters such as the conform factor and the homogeneity index. We stress that the methodology of protocol optimization is valid for single or multiple fractions as well as for intra- and extra-cranial irradiation.

Humans↗

PubMed1999

Brachytherapy optimal planning with application to intravascular radiation therapy.

We have been studying brachytherapy planning with the objective of minimizing the maximum deviation of the delivered dose from prescribed dose bounds for treatment volumes. A general framework for optimal treatment planning is presented and the minmax optimization is formulated as a linear program. Dose rate calculations are based on the dosimetry formulation of the American Association of Physicists in Medicine, Task Group 43. We apply the technique to optimal planning for intravascular brachytherapy of intimal hyperplasia using ultrasound data and 192Ir seeds. The planning includes determination of an optimal dwell-time sequence for a train of seeds that deliver radiation while stepping through the vessel lesion. The results illustrate the advantage of this strategy over the common approach of delivering radiation by positioning a single train of seeds along the whole lesion.

Algorithms↗

PubMed2004

Optimization of PCR based detection of human papillomavirus DNA from urine specimens.

BACKGROUND: Human papillomavirus (HPV) causes cervical cancer. Current screening requires a yearly pelvic exam and Pap smear. However, these procedures are impractical for screening all women at risk for disease. Urine sampling has been successfully utilized to screen for Chlamydia trachomatis (CT) and Neisseria gonorrhoreae (NG) infections and has been considered for HPV DNA detection by several investigators. However, no study to date has been performed to specifically optimize HPV detection in urine. OBJECTIVES: To compare handling and extraction techniques in order to optimize the HPV specific PCR system in urine specimens. STUDY DESIGN: Examination of 10 characteristics that may contribute to PCR inhibition in urine was performed utilizing 10SG mulitstixs. Five different DNA extraction methods were compared in spiked specimens and in 10 clinical specimens. After the optimal extraction technique was identified, concentration of the sample with and without prior dilution was compared to the original protocol. Lastly, specimen handling was compared between immediate processing, refrigerating overnight, or freezing overnight. RESULTS AND CONCLUSIONS: the presence of protein in urine enhanced amplification while nitrites decreased amplification. Of the extraction methods tested, the QIAamp DNA Mini Kit demonstrated the best amplification from urine samples spiked with HPV DNA and clinical specimens. The addition of a dilution step and a concentration step before applying the Qiagen protocol further increased amplification of beta-globin (from 50 to 63%) and the HPV L1 gene (from 13 to 33%). Lastly, refrigerating the specimens at 4 degrees C overnight appears to produce better amplification (62% beta-globin and 17% HPV positive) than either immediate processing (46% beta-globin and 13% HPV+) or freezing the specimen for 24h prior to processing (46% beta-globin and 10% HPV+). In these studies, amplification was low despite optimization. Additional improvements are required prior to clinical application of a urine-based HPV DNA detection system.

DNA, Viral↗

PubMed2003

Optimal conditions for the production of sulfated polysaccharide by marine microalga Gyrodinium impudicum strain KG03.

A marine microalga Gyrodinium impudicum strain KG03 produced sulfated exopolysaccharide designated as p-KG03, which showed a strong antiviral activity against encephalomyocarditis virus (EMCV). To optimize culture conditions for the production of p-KG03, mineral salts, vitamins, plant growth hormones, temperature, pH and light conditions were examined. From this study, M-KG03 medium for the maximum production of p-KG03 was suggested as follows; NH(4)Cl 75 microM, NaH(3)PO(4) 200 microM, NaHCO(3) 50 microM, Na(2)SO(4) 10 microM, FeCl(2) x 6H(2)O 10 microM, MnCl(2) x 4H(2)O 0.1 microM, vitamin B(12) 0.75 microg, naphthalene acetic acid (NAA) 7.5 microg and myo-inositol 200 mg per liter of aged sea water. The optimal temperature and pH were 22.5 degrees C and 8.0, respectively. The optimal light conditions of intensity and period were 150 microE m(-2) s(-1) and 16:8 h light:dark cycle. Finally, the cell growth and p-KG03 production were measured in one liter of M-KG03 medium with 1% CO(2) and 50 ml min(-1) of airflow using two liters airlift balloon type photobioreactor (ABTPR). At these optimal conditions, p-KG03 production and cell growth were 134.6+/-5.9 mg l(-1) and 123,076+/-1,597 cells ml(-1), respectively, representing a 7.7 and 5.1 times compared with f/2 medium with Erlenmeyer flask culture (p-KG03 production 17.5+/-1.3 mg l(-1) and cell growth 24,311+/-1,291 cells ml(-1)).

Animals↗

PubMed1999

Optimal nutrition: calcium, magnesium and phosphorus.

In the past, a major challenge for nutrition research was in defining indicators of nutritional adequacy. More recently, the research base related to the role of nutrition in chronic disease has expanded sufficiently to permit moving beyond deficiency indicators to other indicators with broader functional significance. Thus, nutrition research is faced with the new challenge of defining 'optimal nutrition'. One definition of optimal nutrition with respect to any particular nutrient could be when a functional marker reaches an 'optimal value' or plateau beyond which it is not longer affected by intake or stores of the nutrient. A functional marker of nutrient status could be defined as a physiological or biochemical factor which (1) is related to function or effect of the nutrient in target tissue(s) and (2) is affected by dietary intake or stores of the nutrient (which may include markers of disease risk). Examples of such indicators or markers are those related to risk of chronic diseases such as osteoporosis, CHD, or hypertension. The present review focuses on the concept of optimal nutrition with respect to three nutrients, Ca, Mg and P. However, for P and Mg there are as yet no functional indicators which respond to dietary intake, and in such cases nutrient requirements are established using more traditional approaches, e.g. balance data. For Ca, there has been interest in using maximal Ca retention, which is based on balance data, bone mass measurements and biomarkers of bone turnover as useful functional indicators of the adequacy of Ca intake.

Adolescent↗

PubMed2000

Techniques for the optimization of proteomic strategies based on head column stacking capillary electrophoresis.

Proteomics is the large-scale study of the proteins related to a genome. Presently, proteomic procedures have relied on mass spectrometry as a tool of choice to perform analysis of proteins. Optimization and understanding of the different steps involved in proteomics using mass spectrometry is expensive and time-consuming and, for this reason, have been typically paid insufficient attention. However, optimization becomes a critical issue as we try to analyze ever shrinking amounts of proteins. We present here the development of a technique that allows the rapid, sensitive, semiquantitative, and automated optimization of the processes involved in proteomics. Furthermore, it allows the rapid testing of new methodologies without having to rely on expensive mass spectrometric techniques. The technique, based on head column stacking capillary zone electrophoresis, allows the concentration, separation, and analysis of protein digests at concentrations from high picomoles to subfemtomoles per microliter and sample volumes from a few microliters to a few hundred microliters produced by proteomic processes. Furthermore, the incorporation of UV detection in the system allows the tracking of the relative changes in peptide levels observed during optimization. In addition, all the buffers and solvents used in this technique are compatible with its future coupling to electrospray ionization mass spectrometry. The potential of this technique for the analysis of low-abundance proteins is demonstrated using peptide standards and tryptic digests of standard proteins. Moreover, we exemplify the application of this technique in proteomic prototyping for the rapid and automated study of the procedure of enzymatic digestion of proteins.

Electrophoresis, Capillary↗

PubMed2003

Rotating disk potentiometry for inner solution optimization of low-detection-limit ion-selective electrodes.

The extent of optimization of the lower detection limit of ion-selective electrodes (ISEs) can be assessed with an elegant new method. At the detection limit (i.e., in the absence of primary ions in the sample), one can observe a reproducible change in the membrane potential upon alteration of the aqueous diffusion layer thickness. This stir effect is predicted to depend on the composition of the inner solution, which is known to influence the lower detection limit of the potentiometric sensor dramatically. For an optimized electrode, the stir effect is calculated to be exactly one-half the value of the case when substantial coextraction occurs at the inner membrane side. In contrast, there is no stir effect when substantial ion exchange occurs at the inner membrane side. Consequently, this experimental method can be used to determine how well the inner filling solution has been optimized. A rotating disk electrode was used in this study because it provides adequate control of the aqueous diffusion layer thickness. Various ion-selective membranes with a variety of inner solutions that gave different calculated concentrations of the complex at the inner membrane side were studied to evaluate this principle. They contained the well-examined silver ionophore O,O' '-bis[2-(methylthio)ethyl]-tert-butylcalix[4]arene, the potassium ionophore valinomycin, or the iodide carrier [9]mercuracarborand-3. Stir effects were determined in different background solutions and compared to theoretical expectations. Correlations were good, and the results encourage the use of such stir-effect measurements to optimize ISE compositions for real-world applications. The technique was also found to be useful in estimating the level of primary ion impurities in the sample. For an iodide-selective electrode measured in phosphoric acid, for example, apparent iodide impurity levels were calculated as 5 x 10(-10) M.

Ion-Selective Electrodes↗

PubMed2005

Closed-loop, multiobjective optimization of analytical instrumentation: gas chromatography/time-of-flight mass spectrometry of the metabolomes of human serum and of yeast fermentations.

The number of instrumental parameters controlling modern analytical apparatus can be substantial, and varying them systematically to optimize a particular chromatographic separation, for example, is out of the question because of the astronomical number of combinations that are possible (i.e., the "search space" is very large). However, heuristic methods, such as those based on evolutionary computing, can be used to explore such search spaces efficiently. We here describe the implementation of an entirely automated (closed-loop) strategy for doing this and apply it to the optimization of gas chromatographic separations of the metabolomes of human serum and of yeast fermentation broths. Without human intervention, the Robot Chromatographer system (i) initializes the settings on the instrument, (ii) controls the analytical run, (iii) extracts the variables defining the analytical performance (specifically the number of peaks, signal/noise ratio, and run time), (iv) chooses (via the PESA-II multiobjective genetic algorithm), and (v) programs the next series of instrumental settings, the whole continuing in an iterative cycle until suitable sets of optimal conditions have been established. Genetic programming was used to remove noise peaks and to establish the basis for the improvements observed. The system showed that the number of peaks observable depended enormously on the conditions used and served to increase them by as much as 3-fold (e.g., to over 950 in human serum) while in many cases maintaining or reducing the run time and preserving excellent signal/noise ratios. The evolutionary closed-loop machine learning strategy we describe is generic to any type of analytical optimization.

Fermentation↗

PubMed2004

Aptasensor development: elucidation of critical parameters for optimal aptamer performance.

Aptamers are synthetic oligonucleotides specifically selected to bind a certain target. Thanks to their high affinity and sensitivity, aptamers appear as alternative candidates to antibodies for analytical devices and several assays have been reported. However, and contrary to what happens with DNA probes, the aptamers' ability to bind their targets depends on folding and 3-D structure, which may be affected by the incubation conditions and buffer composition. In this report, a systematic evaluation of the parameters with potential effect on the ELAA (Enzyme Linked Aptamer Assay) performance has been carried out. Additionally, diverse ELAA and mixed ELISA/ELAA formats exploiting the thrombin-binding aptamer have been optimized and their efficiencies compared. ELAA results have been confirmed using nuclear magnetic resonance, electrophoresis, and surface plasmon resonance. Our results indicate that parameters such as immobilization strategy, incubation time/temperature, and buffer composition should be optimized for each aptamer as they affect folding and, thus, binding efficiency. Among the studied assays, the mixed ELISA/ELAA sandwich formats showed the lowest limit of detection observed (<1 nM thrombin), while a competition ELAA appeared as the best assay in terms of high sensitivity (1.8 nM) and short assay time (1 h, 30 min). The elucidation of optimal parameters for assay performance reported here clearly indicates that aptamers are unique structures. Formation of the 3-D structures required for target binding is influenced by variable parameters, and unlike DNA/antibody based assays, there are no general recommendations, with each assay requiring individual optimization of parameters.

Aptamers, Nucleotide↗

PubMed2006

Peak capacity optimization of peptide separations in reversed-phase gradient elution chromatography: fixed column format.

The optimization of peak capacity in gradient elution RPLC is essential for the separation of multicomponent samples such as those encountered in proteomic research. In this work, we study the effect of gradient time (tG), flow rate (F), temperature (T), and final eluent strength (phi(final)) on the peak capacity of separations of peptides that are representative of the range in peptides found in a tryptic digest. We find that there are very strong interactions between the individual variables (e.g., flow rate and gradient time) which make the optimization quite complicated. On a given column, one should first set the gradient time to the longest tolerable and then set the temperature to the highest achievable with the instrument. Next, the flow rate should be optimized using a reasonable but arbitrary value of phi(final). Last, the final eluent strength should be adjusted so that the last solute elutes as close as possible to the gradient time. We also develop an easily implemented, highly efficient, and effective Monte Carlo search strategy to simultaneously optimize all the variables. We find that gradient steepness is an important parameter that influences peak capacity and an optimum range of gradient steepness exists in which the peak capacity is maximized.

Animals↗

PubMedDate not supplied

Effect of transcription promoters on the optimal production of secreted protein in fed-batch reactors.

Production of heterologous proteins by yeast secretion imposes additional factors that need to be considered, which do not appear with production by direct expression. These include additional intracellular polypeptide processing dynamics through the secretory organelles and the protein concentration in the culture medium, which is the usual final destination of the product. Optimal control theory is applied to optimize fed-batch production of secreted protein. We maximize an objective function that includes both total production rate and product concentration. A mutant invertase is chosen as the model heterologous secretory protein. Optimal control control strategies have been obtained for the use of two different promoters for the gene transcription, a dere-pressible SUC2 promoter and a strong glycolytic GPD promoter. With the use of the strong GPD promoter, achieving maximum production occurs on the singular arc of maximum specific growth rate. As the object switches to maximum product concentration, operation occurs for longer periods of time at a slow glucose singular arc condition. The optimal control for maximizing protein production with the weak SUC2 promoter requires transitions between high and low glucose concentrations associated with multiple distinct singular arc conditions. For maximum product concentration, the high concentration branches of the singular arc supporting maximum growth rate and maximum secretion rate disappear. Operation stays essentially on the low glucose concentration branch of the singular arc, which maximizes the protein production rate and minimizes the dilution of the broth product concentration.

Cloning, Molecular↗