Studies on locus content mapping.

Locus content maps are derived from monosomic or disomic chromosomes broken by radiation, shearing, or other clastogen, the fragments being distributed among clones by dilution or incorporation into the cells of another species and scored for segregation of markers. Locus content maps provide evidence about radiosensitivity of chromosome regions, support for order, and approximate location. Omission of the most aberrant and least informative clones increases efficiency of localization. Correct analysis must allow for preferential retention of certain sequences, monosomy or polysomy of donor chromosomes, and error filtration. Combination of these refinements extracts substantially more information from fewer clones. Because of unmodeled peculiarities in the data, the best analysis does not recover the physical map but roughly localizes markers that may be monomorphic and therefore unsuitable for linkage mapping. As with linkage for polymorphic loci, distance in the composite map should be confirmed by physical methods.

Mutants in the Exo I motif of Escherichia coli dnaQ: defective proofreading and inviability due to error catastrophe.

The Escherichia coli dnaQ gene encodes the proofreading 3' exonuclease (epsilon subunit) of DNA polymerase III holoenzyme and is a critical determinant of chromosomal replication fidelity. We constructed by site-specific mutagenesis a mutant, dnaQ926, by changing two conserved amino acid residues (Asp-12-->Ala and Glu-14-->Ala) in the Exo I motif, which, by analogy to other proofreading exonucleases, is essential for the catalytic activity. When residing on a plasmid, dnaQ926 confers a strong, dominant mutator phenotype, suggesting that the protein, although deficient in exonuclease activity, still binds to the polymerase subunit (alpha subunit or dnaE gene product). When dnaQ926 was transferred to the chromosome, replacing the wild-type gene, the cells became inviable. However, viable dnaQ926 strains could be obtained if they contained one of the dnaE alleles previously characterized in our laboratory as antimutator alleles or if it carried a multicopy plasmid containing the E. coli mutL+ gene. These results suggest that loss of proofreading exonuclease activity in dnaQ926 is lethal due to excessive error rates (error catastrophe). Error catastrophe results from both the loss of proofreading and the subsequent saturation of DNA mismatch repair. The probability of lethality by excessive mutation is supported by calculations estimating the number of inactivating mutations in essential genes per chromosome replication.

A simple test of the vicarious trial-and-error hypothesis of hippocampal function.

Vicarious trial-and-error (VTE) is a term that Muenzinger and Tolman used to describe the rat's conflict-like behavior before responding to choice. Recently, VTE was proposed as a mechanism alternative to the concept of "cognitive map" in accounts of hippocampal function. That is, many phenomena of impaired learning and memory related to hippocampal interventions may be explained by behavioral first principles: reduced conflicting, incipient, pre-choice tendencies to approach and avoid. The nonspatial black-white discrimination learning and VTE behavior of the rat were investigated. Hippocampal-lesioned and sham-lesioned animals were trained for 25 days (20 trials per day) starting at 60 days of age. Each movement of the head from one discriminative stimulus to the other was counted as a VTE instance. Lesioned rats had fewer VTEs than sham controls, and the former learned much more slowly or never learned. After learning, VTE frequency declined. Male and female rats showed no significant differences in VTE behavior or discrimination learning.

Mean-value identities as an opportunity for Monte Carlo error reduction

In the Monte Carlo simulation of both lattice field theories and of models of statistical mechanics, identities verified by exact mean values, such as Schwinger-Dyson equations, Guerra relations, Callen identities, etc., provide well-known and sensitive tests of thermalization bias as well as checks of pseudo-random-number generators. We point out that they can be further exploited as control variates to reduce statistical errors. The strategy is general, very simple, and almost costless in CPU time. The method is demonstrated in the twodimensional Ising model at criticality, where the CPU gain factor lies between 2 and 4.

Re-Examining the Stop-Signal Task to Test Competing Theories of AD/HD

The current study tested two competing models of Attention-Deficit/Hyperactivity Disorder (AD/HD), the inhibition and state regulation theories, by conducting fine-grained analyses of the Stop-Signal Task and another putative measure of behavioral inhibition, the Gordon Continuous Performance Test (G-CPT), in a large sample of children and adolescents. The inhibition theory posits that performance on these tasks reflects increased difficulties for AD/HD participants to inhibit prepotent responses. The model predicts that putative stop-signal reaction time (SSRT) group differences on the Stop-Signal Task will be primarily related to AD/HD participants requiring more warning than control participants to inhibit to the stop-signal and emphasizes the relative importance of commission errors, particularly "impulsive" type commissions, over other error types on the G-CPT. The state regulation theory, on the other hand, proposes response variability due to difficulties maintaining an optimal state of arousal as the primary deficit in AD/HD. This model predicts that SSRT differences will be more attributable to slower and/or more variable reaction time (RT) in the AD/HD group, as opposed to reflecting inhibitory deficits. State regulation assumptions also emphasize the relative importance of omission errors and "slow processing" type commissions over other error types on the G-CPT. Overall, results of Stop-Signal Task analyses were more supportive of state regulation predictions and showed that greater response variability (i.e., SDRT) in the AD/HD group was not reducible to slow mean reaction time (MRT) and that response variability made a larger contribution to increased SSRT in the AD/HD group than inhibitory processes. Examined further, ex-Gaussian analyses of Stop-Signal Task go-trial RT distributions revealed that increased variability in the AD/HD group was not due solely to a few excessively long RTs in the tail of the AD/HD distribution (i.e., tau), but rather indicated the importance of response variability throughout AD/HD group performance on the Stop-Signal Task, as well as the notable sensitivity of ex-Gaussian analyses to variability in data screening procedures. Results of G-CPT analyses indicated some support for the inhibition model, although error type analyses failed to further differentiate the theories. Finally, inclusion of primary variables of interest in exploratory factor analysis with other neurocognitive predictors of AD/HD indicated response variability as a separable construct and further supported its role in Stop-Signal Task performance. Response variability did not, however, make a unique contribution to the prediction of AD/HD symptoms beyond measures of motor processing speed in multiple deficit regression analyses. Results have implications for the interpretation of the processes reflected in widely-used variables in the AD/HD literature, as well as for the theoretical understanding of AD/HD.

Clinical validation of an algorithm to correct the error in the keratometric estimation of corneal power for normal eyes

To validate clinically an algorithm for correcting the error in the keratometric estimation of corneal power by using a variable keratometric index of refraction (nk) in a normal healthy population.

Minimizing the IOL Power Error Induced by Keratometric Power

Purpose. To evaluate theoretically in normal eyes the influence on IOL power (PIOL) calculation of the use of a keratometric index (nk) and to analyze and validate preliminarily the use of an adjusted keratometric index (nkadj) in the IOL power calculation (PIOLadj). Methods. A model of variable keratometric index (nkadj) for corneal power calculation (Pc) was used for IOL power calculation (named PIOLadj). Theoretical differences ($PIOL) between the new proposed formula (PIOLadj) and which is obtained through Gaussian optics (PIOL Gauss) were determined using Gullstrand and Le Grand eye models. The proposed new formula for IOL power calculation (PIOLadj) was prevalidated clinically in 81 eyes of 81 candidates for corneal refractive surgery and compared with Haigis, HofferQ, Holladay, and SRK/T formulas. Results. A theoretical PIOL underestimation greater than 0.5 diopters was present in most of the cases when nk = 1.3375 was used. If nkadj was used for Pc calculation, a maximal calculated error in $PIOL of T0.5 diopters at corneal vertex in most cases was observed independently from the eye model, r1c, and the desired postoperative refraction. The use of nkadj in IOL power calculation (PIOLadj) could be valid with effective lens position optimization nondependent of the corneal power. Conclusions. The use of a single value of nk for Pc calculation can lead to significant errors in PIOL calculation that may explain some IOL power overestimations with conventional formulas. These inaccuracies can be minimized by using the new PIOLadj based on the algorithm of nkadj.

Selective SWIFT-R. A Flexible Software-Based Technique for Soft Error Mitigation in Low-Cost Embedded Systems

Commercial off-the-shelf microprocessors are the core of low-cost embedded systems due to their programmability and cost-effectiveness. Recent advances in electronic technologies have allowed remarkable improvements in their performance. However, they have also made microprocessors more susceptible to transient faults induced by radiation. These non-destructive events (soft errors), may cause a microprocessor to produce a wrong computation result or lose control of a system with catastrophic consequences. Therefore, soft error mitigation has become a compulsory requirement for an increasing number of applications, which operate from the space to the ground level. In this context, this paper uses the concept of selective hardening, which is aimed to design reduced-overhead and flexible mitigation techniques. Following this concept, a novel flexible version of the software-based fault recovery technique known as SWIFT-R is proposed. Our approach makes possible to select different registers subsets from the microprocessor register file to be protected on software. Thus, design space is enriched with a wide spectrum of new partially protected versions, which offer more flexibility to designers. This permits to find the best trade-offs between performance, code size, and fault coverage. Three case studies have been developed to show the applicability and flexibility of the proposal.

Algorithm for Correcting the Keratometric Error in the Estimation of the Corneal Power in Eyes With Previous Myopic Laser Refractive Surgery

Purpose: To calculate theoretically the errors in the estimation of corneal power when using the keratometric index (nk) in eyes that underwent laser refractive surgery for the correction of myopia and to define and validate clinically an algorithm for minimizing such errors. Methods: Differences between corneal power estimation by using the classical nk and by using the Gaussian equation in eyes that underwent laser myopic refractive surgery were simulated and evaluated theoretically. Additionally, an adjusted keratometric index (nkadj) model dependent on r1c was developed for minimizing these differences. The model was validated clinically by retrospectively using the data from 32 myopic eyes [range, −1.00 to −6.00 diopters (D)] that had undergone laser in situ keratomileusis using a solid-state laser platform. The agreement between Gaussian (PGaussc) and adjusted keratometric (Pkadj) corneal powers in such eyes was evaluated. Results: It was found that overestimations of corneal power up to 3.5 D were possible for nk = 1.3375 according to our simulations. The nk value to avoid the keratometric error ranged between 1.2984 and 1.3297. The following nkadj models were obtained: nkadj= −0.0064286r1c + 1.37688 (Gullstrand eye model) and nkadj = −0.0063804r1c + 1.37806 (Le Grand). The mean difference between Pkadj and PGaussc was 0.00 D, with limits of agreement of −0.45 and +0.46 D. This difference correlated significantly with the posterior corneal radius (r = −0.94, P < 0.01). Conclusions: The use of a single nk for estimating the corneal power in eyes that underwent a laser myopic refractive surgery can lead to significant errors. These errors can be minimized by using a variable nk dependent on r1c.

Relationship among Corneal Biomechanics, Refractive Error, and Axial Length

Purpose: To evaluate the relationship between different ocular and corneal biomechanical parameters in emmetropic and ametropic healthy white children. Methods: This study included 293 eyes of 293 healthy Spanish children (135 boys and 158 girls), ranging in age from 6 to 17 years. Subjects were divided according to the refractive error: control (emmetropia, 99 children), myopia (100 children), and hyperopia (94 children) groups. In all cases, corneal hysteresis (CH) and corneal resistance factor (CRF) were evaluated with the Ocular Response Analyzer system. Axial length (AL) and mean corneal power were also measured by partial coherence interferometry (IOLMaster), and central corneal thickness (CCT) and anterior chamber depth were measured by anterior segment optical coherence tomography (Visante). Results: Mean (±SD) CH and CRF were 12.12 (±1.71) and 12.30 (±1.89) mm Hg, respectively. Mean (±SD) CCT was 542.68 (±37.20) μm and mean (±SD) spherical equivalent was +0.14 (±3.41) diopters. A positive correlation was found between CH and CRF (p < 0.001), and both correlated as well with CCT (p < 0.0001). Corneal resistance factor was found to decrease with increasing age (p = 0.01). Lower levels of CH were associated with longer AL and more myopia (p < 0.001 and p = 0.001, respectively). Higher values of CH were associated with increasing hyperopia. Significant differences in CH were found between emmetropic and myopic groups (p < 0.001) and between myopic and hyperopic groups (p = 0.011). There were also significant differences in CRF between emmetropic and myopic groups (p = 0.02). Multiple linear regression analysis showed that lower CH and CRF significantly associated with thinner CCT, longer AL, and flatter corneal curvature. Conclusions: The Ocular Response Analyzer corneal biomechanical properties seem to be compromised in myopia from an early age, especially in high myopia.

New Approach for Correction of Error Associated With Keratometric Estimation of Corneal Power in Keratoconus

The aim of this study was to obtain the exact value of the keratometric index (nkexact) and to clinically validate a variable keratometric index (nkadj) that minimizes this error. Methods: The nkexact value was determined by obtaining differences (DPc) between keratometric corneal power (Pk) and Gaussian corneal power (PGauss c ) equal to 0. The nkexact was defined as the value associated with an equivalent difference in the magnitude of DPc for extreme values of posterior corneal radius (r2c) for each anterior corneal radius value (r1c). This nkadj was considered for the calculation of the adjusted corneal power (Pkadj). Values of r1c ∈ (4.2, 8.5) mm and r2c ∈ (3.1, 8.2) mm were considered. Differences of True Net Power with PGauss c , Pkadj, and Pk(1.3375) were calculated in a clinical sample of 44 eyes with keratoconus. Results: nkexact ranged from 1.3153 to 1.3396 and nkadj from 1.3190 to 1.3339 depending on the eye model analyzed. All the nkadj values adjusted perfectly to 8 linear algorithms. Differences between Pkadj and PGauss c did not exceed 60.7 D (Diopter). Clinically, nk = 1.3375 was not valid in any case. Pkadj and True Net Power and Pk(1.3375) and Pkadj were statistically different (P , 0.01), whereas no differences were found between PGauss c and Pkadj (P . 0.01). Conclusions: The use of a single value of nk for the calculation of the total corneal power in keratoconus has been shown to be imprecise, leading to inaccuracies in the detection and classification of this corneal condition. Furthermore, our study shows the relevance of corneal thickness in corneal power calculations in keratoconus.

Estimation of the Central Corneal Power in Keratoconus: Theoretical and Clinical Assessment of the Error of the Keratometric Approach

Purpose: The aim of this study was to analyze theoretically the errors in the central corneal power calculation in eyes with keratoconus when a keratometric index (nk) is used and to clinically confirm the errors induced by this approach. Methods: Differences (DPc) between central corneal power estimation with the classical nk (Pk) and with the Gaussian equation (PGauss c ) in eyes with keratoconus were simulated and evaluated theoretically, considering the potential range of variation of the central radius of curvature of the anterior (r1c) and posterior (r2c) corneal surfaces. Further, these differences were also studied in a clinical sample including 44 keratoconic eyes (27 patients, age range: 14–73 years). The clinical agreement between Pk and PGauss c (true net power) obtained with a Scheimpflug photography–based topographer was evaluated in such eyes. Results: For nk = 1.3375, an overestimation was observed in most cases in the theoretical simulations, with DPc ranging from an underestimation of 20.1 diopters (D) (r1c = 7.9 mm and r2c = 8.2 mm) to an overestimation of 4.3 D (r1c = 4.7 mm and r2c = 3.1 mm). Clinically, Pk always overestimated the PGauss c given by the topography system in a range between 0.5 and 2.5 D (P , 0.01). The mean clinical DPc was 1.48 D, with limits of agreement of 0.71 and 2.25 D. A very strong statistically significant correlation was found between DPc and r2c (r = 20.93, P , 0.01). Conclusions: The use of a single value for nk for the calculation of corneal power is imprecise in keratoconus and can lead to significant clinical errors.

Error induced by the estimation of the corneal power and the effective lens position with a rotationally asymmetric refractive multifocal intraocular lens

AIM: To evaluate the prediction error in intraocular lens (IOL) power calculation for a rotationally asymmetric refractive multifocal IOL and the impact on this error of the optimization of the keratometric estimation of the corneal power and the prediction of the effective lens position (ELP). METHODS: Retrospective study including a total of 25 eyes of 13 patients (age, 50 to 83y) with previous cataract surgery with implantation of the Lentis Mplus LS-312 IOL (Oculentis GmbH, Germany). In all cases, an adjusted IOL power (PIOLadj) was calculated based on Gaussian optics using a variable keratometric index value (nkadj) for the estimation of the corneal power (Pkadj) and on a new value for ELP (ELPadj) obtained by multiple regression analysis. This PIOLadj was compared with the IOL power implanted (PIOLReal) and the value proposed by three conventional formulas (Haigis, Hoffer Q and Holladay). RESULTS: PIOLReal was not significantly different than PIOLadj and Holladay IOL power (P>0.05). In the Bland and Altman analysis, PIOLadj showed lower mean difference (-0.07 D) and limits of agreement (of 1.47 and -1.61 D) when compared to PIOLReal than the IOL power value obtained with the Holladay formula. Furthermore, ELPadj was significantly lower than ELP calculated with other conventional formulas (P<0.01) and was found to be dependent on axial length, anterior chamber depth and Pkadj. CONCLUSION: Refractive outcomes after cataract surgery with implantation of the multifocal IOL Lentis Mplus LS-312 can be optimized by minimizing the keratometric error and by estimating ELP using a mathematical expression dependent on anatomical factors.