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PubMed2005

Gene expression during sex determination reveals a robust female genetic program at the onset of ovarian development.

The primary event in mammalian sexual development is the differentiation of the bipotential gonads into either testes or ovaries. Our understanding of the molecular pathways specifying gonadal differentiation is still incomplete. To identify the initial molecular changes accompanying gonadal differentiation in mice, we have performed a large-scale transcriptional analysis of XX and XY Sf1-positive gonadal cells during sex determination. In both male and female genital ridges, a robust genetic program is initiated pre-dating the first morphological changes of the differentiating gonads. Between E10.5 and E13.5, 2306 genes were expressed in a sex-specific manner in the somatic compartment of the gonads; 1223 were overexpressed in XX embryos and 1083 in XY embryos. Although sexually dimorphic genes were scattered throughout the mouse genome, we identified chromosomal regions hosting clusters of genes displaying similar expression profiles. The cyclin-dependent kinase inhibitors Cdkn1a and Cdkn1c are overexpressed in XX gonads at E11.5 and E12.5, suggesting that the increased proliferation of XY gonads relative to XX gonads may result from the overexpression of cell cycle inhibitors in the developing ovaries. These studies define the major characteristics of testicular and ovarian transcriptional programs and reveal the richness of signaling processes in differentiation of the bipotential gonads into testes and ovaries.

Animals↗
PubMed2005

A fast and robust quantitative time-lapse assay for cell migration.

We describe a simple and widely applicable method to measure cell migration in time-lapse sequences of fluorescently labeled cells in culture. Briefly, binarized cell images obtained after thresholding were cumulatively projected, and the covered areas were measured. This procedure determines the time course of the track area successively covered by the cell population. Under conditions where cell growth is negligible, a robust index of cell motility is derived from normalized plots for the displacement of cells over time. We applied this method to quantitatively examine the migration of B35 neuroblastoma cells transiently expressing GFP and to C6 glioma cells after staining with Hoechst 33258. This sensitive assay detected the influence of agents which inhibit actin polymerization (cytochalasin B) or interfere with the maintenance of cell polarity (methyl-beta-cyclodextrin) on cell migration. Thus, this assay is a versatile tool to measure quickly the migration of different cell types using different labeling strategies.

Animals↗
PubMed2026

Unraveling cadaverine toxicity effect to guide the engineering of robust strain.

End-product inhibition represents a major challenge in the microbial synthesis of various value-added chemicals. Cadaverine, a key monomer for polyamide synthesis, exhibits severe cytotoxicity, limiting its high-titer biosynthesis. Here, transcriptomic analysis and genome-wide library screening were integrated to systematically elucidate the cytotoxic mechanisms of cadaverine in Escherichia coli (E. coli) and identify beneficial genes for enhanced tolerance and overproduction. Transcriptomic analysis revealed that high concentrations of cadaverine disrupted cell membrane integrity and impaired oxidative phosphorylation, leading to redox imbalance and reactive oxygen species (ROS) accumulation. Subsequent genome-wide screening further confirmed these toxicity mechanisms and uncovered crucial cellular defense strategies. Functional validation highlighted the important role of NikR, UbiE, and YcbX in enhancing membrane integrity, restoring respiratory function and ROS homeostasis, or scavenging 6-N-hydroxylaminopurine (6-HAP) to prevent DNA damage. Among these, YcbX emerged as the most effective target for improving production. Consequently, we constructed a robust E. coli strain by implementing a dynamic regulation system for YcbX expression under cadaverine-responsive promoters, which significantly enhanced cadaverine biosynthesis to 87.2 g/L (a 46.8% enhancement). This work provides an in-depth understanding of cadaverine toxicity and tolerance, offering valuable targets and strategies for the rational design of high-performance microbial cell factories for diamines.

6-HAP clearance↗
PubMed2025

Identification of a robust promoter in mouse and human hepatocytes by in vivo biopanning of a barcoded AAV library.

Recombinant adeno-associated viruses (AAVs) are leading vectors for in vivo human gene therapy. An integral vector element is promoters, which control transgene expression in either a ubiquitous or cell-type-selective manner. Identifying optimal capsid-promoter combinations is challenging, especially when considering on- versus off-target expression. Here, we report a pipeline for in vivo promoter biopanning in AAV building on our AAV capsid barcoding technology and illustrate its potential by screening 53 promoters in 16 murine tissues using an AAV9 vector. Surprisingly, the 2.2-kb human glial fibrillary acidic protein (GFAP) promoter was the top hit in the liver, where it outperformed robust benchmarks such as the human α-1-antitrypsin promoter or the clinically used liver-specific promoter 1 (LP1). Analysis of hepatic cell populations revealed preferred GFAP promoter activity in hepatocytes. Notably, the GFAP promoter also surpassed the LP1 and cytomegalovirus promoters in human hepatocytes engrafted in an immune-deficient mouse. These findings establish the GFAP promoter as an exciting alternative for research and clinical applications requiring efficient and specific transgene expression in hepatocytes. Our pipeline expands the arsenal of technologies for high-throughput in vivo screening of viral vector components and is compatible with capsid barcoding, facilitating the combinatorial interrogation of complex AAV libraries.

Dependovirus↗
PubMed2006

Mis-specified and non-robust mortality risk models for nasopharyngeal cancer in the National Cancer Institute formaldehyde worker cohort study.

An IARC (International Agency for Research on Cancer) working group categorized formaldehyde as a human carcinogen (Group 1) in 2004. A major component of the epidemiologic evidence evaluated by IARC to reach this decision was the analysis published by Hauptmann et al. [Hauptmann, M., Lubin, J. H., Stewart, P. A., Hayes, R. B., Blair, A. 2004. Mortality from solid cancers among workers in formaldehyde industries. Am. J. Epidemiol. 159, 1117-1130.] of the National Cancer Institute (NCI) historical cohort comprising industrial workers exposed to formaldehyde in 10 U.S. plants. The NCI authors emphasized the relationship found between highest formaldehyde peak exposure and death from nasopharyngeal cancer (NPC). We performed two additional types of re-analyses of the NCI cohort data with focus on peak exposure and NPC mortality. The analyses were aimed at (1) investigating whether the model specification chosen by Hauptmann et al. (2004) was appropriate (interaction assessment) and (2) exploring the degree of instability of the risk estimates for NPC in relation to highest peak exposure (sensitivity analysis). Hauptmann et al. (2004) failed to account for an important interaction structure between plant group and the exposure variable that prohibits a generalization of formaldehyde effects within the NCI cohort and, in particular, beyond the NCI cohort. In addition, our sensitivity analysis demonstrates considerable uncertainties in the risk estimates and points convincingly to instability problems particularly related to Plant 1. Even a simple sensitivity model taking only one additional death into account produced a variation of the risk estimates beyond the instability conveyed by standard confidence intervals. The results of our current reanalysis of the NCI study do not support NCI's suggestion of a causal association with formaldehyde exposure and nasopharyngeal cancer. The decision by the IARC working group to reclassify formaldehyde as a Group 1 substance was clearly premature considering: (1) the missing evidence of an NPC excess from the large British and NIOSH cohort studies; (2) the absence of an association with formaldehyde and NPC in the independent and expanded study of Plant 1; and (3) the mis-specified and non-robust internal analysis of the NCI cohort study brought to light in our current re-analysis. Thus, the 2004 IARC decision to reclassify formaldehyde as a Group 1 substance should be reconsidered.

Adenocarcinoma↗
PubMed1998

Microbial invasion of the amniotic cavity with Ureaplasma urealyticum is associated with a robust host response in fetal, amniotic, and maternal compartments.

OBJECTIVE: Ureaplasma urealyticum is the microorganism most frequently isolated from the amniotic fluid of women with preterm labor and preterm premature rupture of the membranes, yet the significance of amniotic fluid infection exclusively caused by this microorganism is unclear. This study was conducted to examine the presence and intensity of the inflammatory response in the fetal, amniotic, and maternal compartments in patients with preterm premature rupture of membranes and amniotic fluid infection with U urealyticum. STUDY DESIGN: One hundred twenty patients with preterm premature rupture of the membranes who delivered preterm neonates (gestational age </=36 weeks) within 5 days of amniocentesis were included. Amniotic fluid was cultured for aerobic and anaerobic bacterias and mycoplasmas. The intensity of the inflammatory response was evaluated by amniotic fluid concentrations of interleukin-6, tumor necrosis factor-alpha, interleukin-1beta, amniotic fluid white blood cell count, histologic chorioamnionitis, and interleukin-6 concentrations of umbilical cord plasma at birth. Cytokines were measured by sensitive and specific immunoassays. RESULTS: The prevalence of a positive amniotic fluid culture in which the only microbial isolate was U urealyticum was 21% (25/120) and that of positive cultures with other or mixed microorganisms was 9% (11/120). Intrauterine inflammatory response was significantly more intense in patients with positive amniotic fluid cultures limited to U urealyticum than in those with a negative culture (median and range of amniotic fluid interleukin-6, 13.4 [0.7-115.2] ng/mL vs 0.9 [0.001-137.2] ng/mL; median and range of amniotic fluid tumor necrosis factor-alpha, 85.5 [0.9-1600] pg/mL vs 2.4 [0-1142] pg/mL; median and range of amniotic fluid interleukin-1beta, 274.0 [0.3->80,000] pg/mL vs 3.4 [0-1449] pg/mL; median and range of amniotic fluid white blood cell count, 306 [0-19,764] cells/mm3 vs 3 [0-7956] cells/mm3; median and range of cord interleukin-6, 20.0 [2. 3-1199.6] pg/mL vs 6.7 [0-5550] pg/mL; histologic chorioamnionitis, 100% [22/22] vs 42% [30/72]; P <.01 for each) but was similar to values of patients with a positive amniotic fluid culture for other bacteria or mixed microorganisms. CONCLUSION: Patients with preterm premature rupture of membranes and microbial invasion of the amniotic cavity with U urealyticum are associated with a robust host inflammatory response in the fetal, amniotic, and maternal compartments.

Adult↗
PubMed2003

Robust regression-based analysis of drug-nucleic acid binding.

Outlier detection can be very important in analyzing data from Scatchard plots. In this study, a robust (outlier-resistant) regression procedure was used in conjunction with a Scatchard plot to study the binding of the methylphenazinium cation with double-stranded DNA. The procedures, their results, and their advantages are discussed.

DNA↗
PubMed2002

A turbo engine with automatic transmission? How to marry chemicomotion to the subtleties and robustness of life.

Most genomes are much more complex than required for the minimum chemistry of life. Evolution has selected sophistication more than life itself. Could this also apply to bioenergetics? We first examine mechanisms through which bioenergetics could deliver sophistication. We illustrate possible benefits of the turbo-charging of catabolic pathways, of loose coupling, low-gear catabolism, automatic transmission in energy coupling, and of homeostasis. Mechanisms for such phenomena may reside at the level of individual proton pumps, or consist of rerouting of electrons over parallel pathways. The mechanisms may be confined to preexisting components, or involve the plasticity of gene expression that is so characteristic of most living organisms. These possible benefits lead us to the conjecture that also bioenergetics has evolved more for sophistication than for necessity. We next discuss a hitherto unresolved enigma, i.e. that bioenergetics does not seem to be critical for the physiological state. To decide on how critical bioenergetics is, we quantified the control exerted by catabolism on important physiological functions such as growth rate and growth yield. We also determined whether a growth inhibition mostly affected bioenergetics (catabolism) or anabolism; if ATP increases with growth rate, then growth should be considered energy (catabolism) limited. The experimental results for Escherichia coli pinpoint the enigma: its energy metabolism (catabolism) is not critical for growth rate. These results might suggest that because it has no direct control over cell function, bioenergetics is unimportant. Paradoxically however, in biology, highly important mechanisms tend to have little control on cell function, precisely because of that importance. Sophistication in terms of homeostatic mechanisms has evolved to guarantee robustness of the most important functions: The most important mechanisms are redundant in biology. Bioenergetics may be an excellent example of this paradox, in line with the above conjecture. It may be highly important and sophisticated. We then discuss work that has begun to focus on the sophistication of bioenergetics. Homeostasis of the energetics of DNA structure in E. coli is extensive. It relies both on preexisting components and on responsive gene expression. The vastly parallel electron-transfer network of Paracoccus denitrificans engages in sophisticated dynamic and hierarchical regulation. The growth yield of the organism can depend on which terminal oxidases are active. Effective proton translocation may vary due to rerouting of electrons. We conclude that much sophistication of bioenergetics will be discovered in this era of functional genomics.

Adenosine Triphosphate↗
PubMed2001

Robust, high-resolution, whole cell patch-clamp capacitance measurements using square wave stimulation.

High-resolution, whole cell capacitance measurements are usually performed using sine wave stimulation using a single frequency or a sum of two frequencies. We present here a high-resolution technique for whole-cell capacitance measurements based on square-wave stimulation. The square wave represents a sum of sinusoidal frequencies at odd harmonics of the base frequency, the amplitude of which is highest for the base frequency and decreases as the frequency increases. The resulting currents can be analyzed by fitting the current relaxations with exponentials, or by a phase-sensitive detector technique. This method provides a resolution undistinguishable from that of single-frequency sine wave stimulation, and allows for clear separation of changes in capacitance, membrane conductance, and access resistance. In addition, it allows for the analysis of more complex equivalent circuits as associated with the presence of narrow fusion pores during degranulation, tracking many equivalent circuit parameters simultaneously. The method is insensitive to changes in the reversal potential, pipette capacitance, or widely varying cell circuit parameters. It thus provides important advantages in terms of robustness for measuring cell capacitances, and allows analysis of complicated changes of the equivalent circuits.

Animals↗
PubMed2003

Robust biased Brownian dynamics for rate constant calculation.

A reaction probability is required to calculate the rate constant of a diffusion-dominated reaction. Due to the complicated geometry and potentially high dimension of the reaction probability problem, it is usually solved by a Brownian dynamics simulation, also known as a random walk or path integral method, instead of solving the equivalent partial differential equation by a discretization method. Building on earlier work, this article completes the development of a robust importance sampling algorithm for Brownian dynamics-i.e., biased Brownian dynamics with weight control-to overcome the high energy and entropy barriers in biomolecular association reactions. The biased Brownian dynamics steers sampling by a bias force, and the weight control algorithm controls sampling by a target weight. This algorithm is optimal if the bias force and the target weight are constructed from the solution of the reaction probability problem. In reality, an approximate reaction probability has to be used to construct the bias force and the target weight. Thus, the performance of the algorithm depends on the quality of the approximation. Given here is a method to calculate a good approximation, which is based on the selection of a reaction coordinate and the variational formulation of the reaction probability problem. The numerically approximated reaction probability is shown by computer experiments to give a factor-of-two speedup over the use of a purely heuristic approximation. Also, the fully developed method is compared to unbiased Brownian dynamics. The tests for human superoxide dismutase, Escherichia coli superoxide dismutase, and antisweetener antibody NC6.8, show speedups of 17, 35, and 39, respectively. The test for reactions between two model proteins with orientations shows speedups of 2578 for one set of configurations and 3341 for another set of configurations.

Antigen-Antibody Complex↗
PubMed1983

Robust estimation in pulse fluorometry. A study of the method of moments and least squares.

Most laboratories use least-squares iterative reconvolution (LSIR) as a routine method for estimating decay parameters in pulse fluorometric data. It is shown here, however, that LSIR is very sensitive to small amounts of error in the data whenever two decays become too close to one another, or whenever analyses of three decays are attempted. In such cases, inferior methods of estimating integrals, small zero point shifts, or small errors in the measured exciting light will result in failures of least squares, where the method of moments, with moment index displacement and lambda invariance testing, will succeed. The method of moments is therefore robust with respect to such errors while least squares is not.

Spectrometry, Fluorescence↗
PubMed1998

A robust increase in expression of arc gene, an effector immediate early gene, in the rat brain after acute and chronic methamphetamine administration.

The effect of acute and chronic administration of methamphetamine (METH) on the levels of activity-regulated cytoskeleton-associated protein (arc), an effector-immediate early gene, mRNA has been investigated in rat brain using in situ hybridization. Levels of arc mRNAs in the brain regions examined increased significantly from 0.5-1 h after an acute METH (4 mg/kg) administration compared with basal levels. The increase in arc mRNA continued by 3 h, and then subsided to basal levels by 6 h. The degree of increase in arc mRNA and the peak time after METH administration varied according to brain area. Arc mRNA in cerebral cortices showed robust increase 1 h after METH administration. In the striatum and hippocampus, it showed earlier and later increase, respectively, and its degree of both was less than in the cortices. Microscopic examination revealed that the METH-induced arc mRNAs in the parietal cortex were enriched in layers IV and VI, and those in the striatum existed mainly in the medium-sized neuron. Pretreatment with either 0.5 mg/kg SCH23390 or 0.25 mg/kg MK-801 almost completely blocked the enhanced striatal arc mRNA levels induced by acute METH administration, whereas such pretreatments only partially reduced the effect of METH in the cerebral cortical regions. In the chronic treatment experiment, the arc mRNA levels of the group that received chronic treatment with METH followed by a METH challenge showed an increase like seen after acute METH administration. Since previous studies proposed that arc is one of cytoskeleton-associated proteins and is selectively localized in neural dendrites, the results of the present study suggested that arc may play an important role in the synaptic plasticity underlying METH-induced adaptational changes including behavioral sensitization.

Animals↗
PubMed2003

Reasoning about a hidden object after a delay: evidence for robust representations in 5-month-old infants.

The present research examined two alternative interpretations of violation-of-expectation findings that young infants can represent hidden objects. One interpretation is that, when watching an event in which an object becomes hidden behind another object, infants form a prediction about the event's outcome while both objects are still visible, and then check whether this prediction was accurate. The other interpretation is that infants' initial representations of hidden objects are weak and short-lived and as such sufficient for success in most violation-of-expectation tasks (as objects are typically hidden for only a few seconds at a time), but not more challenging tasks. Five-month-old infants succeeded in reasoning about the interaction of a visible and a hidden object even though (1) the two objects were never simultaneously visible, and (2) a 3- or 4-min delay preceded the test trials. These results provide evidence for robust representations of hidden objects in young infants.

Child Development↗
PubMed2001

Lack of robust anticonvulsant effects of muscimol microinfusions in the anterior substantia nigra of kindled rats.

The substantia nigra pars reticulata is thought to control the spread of seizures in various seizure models. Potentiation of gamma-aminobutyrate (GABA)-mediated transmission in this region by intranigral administration of drugs such as muscimol has been shown to inhibit seizure propagation in such models, including the kindling model of epilepsy. More recent studies have shown that the effects on seizures are site-specific within the substantia nigra pars reticulata. Using flurothyl to induce clonic seizures, it was reported that bilateral microinfusions of muscimol into the anterior substantia nigra pars reticulata were anticonvulsant, while similar infusions into the posterior pars reticulata were proconvulsant. This prompted us to reevaluate the effects of intranigral muscimol in the kindling model with particular emphasis on the anterior substantia nigra pars reticulata. In amygdala kindled rats, muscimol was bilaterally infused into the anterior pars reticulata at doses of either 60 or 120 ng. Thirty minutes later, the threshold for induction of afterdischarges in the amygdala and the threshold for generalized seizures were determined in each rat. Furthermore, severity and duration of seizures at threshold currents were recorded. Unexpectedly, muscimol failed to increase seizure thresholds or to significantly reduce seizure severity or duration of motor seizures, although there was a moderate reduction in motor seizure duration in several rats. The data indicate that, in contrast to flurothyl seizures, in kindled rats the anterior pars reticulata of the substantia nigra is not a site at which muscimol causes robust anticonvulsant effects.

Amygdala↗
PubMed2003

A robust animal model of state anxiety: fear-potentiated behaviour in the elevated plus-maze.

Fear (i.e., decreased percentage time spent on open-arm exploration) in the elevated plus-maze can be potentiated by prior inescapable stressor exposure, but not by escapable stress. The use of fear-potentiated plus-maze behaviour has several advantages as compared to more traditional animal models of anxiety. (a) In contrast to the traditional (spontaneous) elevated plus-maze, which measures innate fear of open spaces, fear-potentiated plus-maze behaviour reflects an enhanced anxiety state (allostatic state). This "state anxiety" can be defined as an unpleasant emotional arousal in face of threatening demands or dangers. A cognitive appraisal of threat is a prerequisite for the experience of this type of emotion. (b) Depending on the stressor used (e.g., fear of shock, predator odour, swim stress, restraint, social defeat, predator stress (cat)), this enhanced anxiety state can last from 90 min to 3 weeks. Stress effects are more severe when rats are isolated in comparison to group housing. (c) Drugs can be administered in the absence of the original stressor and after stressor exposure. As a consequence, retrieval mechanisms are not affected by drug treatment. (d) Fear-potentiated plus-maze behaviour is sensitive to proven/putative anxiolytics and anxiogenics which act via mechanisms related to the benzodiazepine-gamma-aminobutyric acid receptor, but it is also sensitive to corticotropin-releasing receptor antagonists and glucocorticoid receptor antagonists and serotonin receptor agonists/antagonists complex (high predictive validity). (e) Fear-potentiated plus-maze behaviour is very robust, and experiments can easily be replicated in other labs. (f) Fear-potentiated plus-maze behaviour can be measured both in males and females. (g) Neural mechanisms involved in contextual fear conditioning, fear potentiation and state anxiety can be studied.Thus, fear-potentiated plus-maze behaviour may be a valuable measure in the understanding of neural mechanisms involved in the development of anxiety disorders and in the search for novel anxiolytics. Finally, the involvement of corticotropin-releasing factor and corticosteroid-corticotropin-releasing factor interactions in the production of fear-potentiated plus-maze behaviour are discussed.

Animals↗
PubMed2002

Model predictive control helps to regulate slow processes--robust barrel temperature control.

Slow temperature control is a challenging control problem. The problem becomes even more challenging when multiple zones are involved, such as in barrel temperature control for extruders. Often, strict closed-loop performance requirements (such as fast startup with no overshoot and maintaining tight temperature control during production) are given for such applications. When characteristics of the system are examined, it becomes clear that a commonly used proportional plus integral plus derivative (PID) controller cannot meet such performance specifications for this kind of system. The system either will overshoot or not maintain the temperature within the specified range during the production run. In order to achieve the required performance, a control strategy that utilizes techniques such as model predictive control, autotuning, and multiple parameter PID is formulated. This control strategy proves to be very effective in achieving the desired specifications, and is very robust.

Computer Simulation↗
PubMed2003

Robust quadratic stabilization applied to design of continuous-time and discrete-time observers.

In this paper, an application of a robust quadratic stabilization algorithm (RQSA) to continuous-time and discrete-time observers is presented. The RQSA is based on checking end points of a bounding hyperpolyhedron. The RQSA applied to observers is introduced, and implemented for a simplified car model, in both continuous-time and discrete-time case. The paper concludes that the RQSA is feasible to estimate unavailable states, even though there are structured uncertainties in the system matrix and in the measurement matrix.

Journal Article↗
PubMed2004

Low order robust controller design for preserving Hinfinity performance: genetic algorithm approach.

This paper investigates the design of low order robust controllers based on an Hinfinity performance index using a real-code genetic algorithm. In Hinfinity controller design, the major disadvantage of the existing methods is that they lead to high-order controllers. This is the gap between theory and practice. Therefore the purpose of this paper is to design a low order controller with similar performance to the Hinfinity optimal controllers, which can find sufficiently wide use in engineering practice. We first design the Hinfinity optimal controller using Glover and Doyle's results, and obtain the corresponding performance index gamma. Second, the desired low order controller with several parameters is chosen, e.g., a first-order controller, or a PID controller. Finally, we use the real-code genetic algorithm to find the optimal controller parameters that preserve the performance index y. Computational simulations illustrate the effectiveness of the proposed approach.

Journal Article↗