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Robust error-minimization in the genetic code across physicochemical metrics and variant codes: A graph-theoretic analysis in GF(2)6.

The standard genetic code reduces the impact of point mutations, but the robustness of this property across physicochemical metrics, naturally occurring variant codes, and codon-reassignment mechanisms remains incompletely quantified. Embedding the 64 codons in GF(2)6 represents the hypercube Q6 as a coordinate-dependent subgraph of the encoding-independent single-nucleotide mutation graph H(3,4), and enables continuous &#x3c1;-interpolation between the two. Under a quartet-pattern shuffle null (n=10,000), the standard code is significantly low-cost across four established, code-independent physicochemical distance metrics with partially overlapping content (Grant ham p=0.0062; Miyata p<0.001; Woese polar requirement p=0.003; Kyte-Doolittle hydropathy p=0.001), and the signal strengthens monotonically as &#x3c1; moves Q6&#x2192;H(3,4). A structure-aware sensitivity analysis under the alignment-derived ProtSub matrix (Jia & Jernigan 2021) yields the most extreme percentile of any measure tested (p=0.0004; all five p-values pass Bonferroni at &#x3b1;=0.05). Across the 27 NCBI translation tables, near-optimality is preserved: 11 of 12 informative-distance variants retain top-5% placement after BH-FDR correction. Natural codon reassignments avoid disrupting codon-family connectivity: under the encoding-independent H(3,4) adjacency, observed events are topology-breaking at relative risk 0.32 versus the candidate landscape (permutation p&#x2264;10-4). The H(3,4) result is stable by construction; the Q6 decomposition is representation-specific and fails to show depletion under 8 of 24 base-to-bit encodings, so we report H(3,4) as the primary test and Q6 as a sensitivity. Event-level conditional-logit modelling shows that topology avoidance and local physicochemical cost provide complementary, only weakly correlated signal (rs=0.15), and that topology adds explanatory value beyond physicochemistry under both Q6 and encoding-independent H(3,4) adjacency. Retrospective reanalysis of nine genome-recoding datasets is consistent with codon-family topology operating as an evolutionary-trajectory constraint distinct from acute engineering fitness. The contribution is the second axis: code evolution is jointly constrained by physicochemical smoothness and codon-family topological integrity, and these two constraints are partly independent.

Codon reassignment

Minimizing biopsy error.

Several factors influence substantially the order of accuracy of oral biopsy procedures. This paper evaluates some of these factors and suggests methods whereby accuracy can be improved. The surgeon's responsibility extends beyond the operating theater and into the laboratory if maximum value is to be derived from each biopsy specimen. It is suggested that present sucess rates of surgical treatment of oral carcinoma can be improved by attention to laboratory procedures by the clinician.

Biopsy

The genetic code at the balance point of error and demand.

The origin and organizing principles of the genetic code remain central problems in molecular evolution. The low probability of the natural codon-to-amino acid mapping arising by chance has spurred the hypothesis that its structure is optimized for robustness to mutations and translational errors. For the construction of effective molecular machines, the repertoire of encoded amino acids must also be diverse enough in physicochemical features. Here, we examine whether the standard genetic code can be understood as a near-optimal solution balancing these two objectives: minimizing error load and aligning codon assignments with the naturally occurring amino acid composition. Using simulated annealing, we explore this trade-off across a broad range of parameters. We find that the standard genetic code resides near an optimum in the fitness landscape of possible genetic codes. The degeneracy of the code plays a dual role, minimizing mistranslation errors while matching codon multiplicity to amino acid usage frequencies. As a result, uniform codon usage alone is sufficient to recover the empirical amino acid composition, without any additional bias. It is a highly effective solution that balances fidelity against resource availability constraints. A comparative analysis of natural variants also reveals a functional decoupling: error robustness acts as a rigid global constraint determined by code topology, whereas compositional alignment serves as a more flexible variable that adapts to lineage-specific demands. These results support a multi-objective optimization framework in which the genetic code reflects a balance between translational fidelity and proteomic demand.

Genetic Code

[Use of paper indicator discs for determining the minimal inhibitory concentration of antibiotics].

Sensitivity of clinical strains of Staphylococcus and some Enterobacteriaceae to a number of widely used antibiotics was compared simultaneously with the use of two methods, i. e. the agar diffusion method and the method of serial dilutions. Regularities in distribution of the staphylococcal strains according to their sensitivity to antibiotics, such as erythromycin, benzylpenicillin, levomycetin and others were also studied with respect to every year using indicator paper discs. Interrelation observed during the comparison of the microbial sensitivity with the use of the two assay methods provided elaboration of the criteria for classification of the strains as "resistant" or "sensitive". The differentiation boarder for these two groups was determined according to the principle of the assay error minimization. A necessity of using standard dry media for specification of individual characteristics of various drugs in estimation of the microbial sensitivity to them by the agar diffusion method is emphasized.

Anti-Bacterial Agents

Screening methods using sulfamethazine for determining acetylator phenotype.

Analysis of sulfamethazine (SMZ) kinetics in man has revealed complexities including wide intersubject variability. In our study, an attempt was made to assess the potential influence of changes in nonmetabolic parameters (absorption and urinary elimination rate constants) on the markers of acetylation capacity normally used in clinical screening procedures to determine phenotype. Seven normal subjects were classified as slow (SA) or fast acetylators (FA) according to their metabolic rate constant for SMZ (Km), plasma SMZ half-life, and percentage of N-acetyl SMZ in a 6-hr blood sample (PI6), a 5- to 6-hr urine collection (UI5--6), or a 6-hr total urine collection (UI6). Computer simulations were applied to baseline SMZ kinetic data from these subjects, varying nonmetabolic kinetic parameters over experimentally defined ranges singly, or in parallel with 1 or more of the other parameters. The simulations indicate that all the usual phenotyping procedures were sensitive to changes in absorption and urinary elimination rate constants. While these predictions require experimental confirmation, results show that the PI6 method is least sensitive to such changes, suggesting this method may minimize errors in phenotyping screening.

Absorption

Postweaning environmental stimulation and somesthetic performance in rats sustaining cortical lesions at maturity.

Rats were enucleated at 28 days of age and were assigned to complex or relatively barren tactile environments for the duration of the experiment. Approximately half of the animals in each group received large, bilateral lesions of the somatosensory cortex when they were 60 days of age, and the remainder underwent sham operations. Twenty days later all groups were tested for the ability to master a series of tactile discriminations. Statistical tests revealed a highly significant lesion effect, but no environment or lesion x environment interaction effects. These sensory discriminative findings stand in contrast to some earlier reports which have shown that environmental complexity provided prior to or following other forebrain lesions can minimize error scores on simple learning tasks.

Animals

The role of the pathologist in diagnosis and surgical decision making in hyperparathyroidism.

Hyperparathyroidism has been diagnosed with increasing frequency in recent decades. The concomitant awareness that the disease may be the cause of a concealed morbidity and even an increased mortality has resulted in more liberal indications for surgery. Many patients currently undergo surgery on the grounds of only mild hypercalcemia and in the absence of any apparent clinical symptoms. This policy of early surgical treatment has emphasized the importance of a histopathological parathyroid diagnosis, since many of these patients exhibit chief cell hyperplasia and minimal glandular enlargement. Light microscopic examination of frozen sections stained with hematoxylin-eosin and with stains for demonstration of cytoplasmic fat in the parathyroid chief cells, and appropriate weight estimates of the parathyroid glands, constitute the conventional, intra-operative basis for the diagnosis. The use of specific antiparathyroid antibodies is an important new tool in the histopathological parathyroid examination, mainly because of the ability to demonstrate the cause of increased parathyroid hormone release from the pathological parathyroid tissue. A careful histopathological examination in combination with gross inspection of the parathyroid glands by an experienced eye should contribute to adequate surgical treatment and minimize errors in operative management in patients with hyperparathyroidism.

Adenoma

Occurrence and significance of echocardiographically demonstrated tricuspid valve prolapse.

Echocardiograms from 562 patients were examined for evidence of the pattern of tricuspid valve prolapse. Criteria for the diagnosis can be established similar to those applicable to mitral prolapse. In 500 consecutive patients without mitral valve prolapse, there were no cases of isolated tricuspid valve prolapse. Eleven of 53 (21%) patients with mitral valve prolapse also had tricuspid valve prolapse. Four of six (67%) patients with Marfan's syndrome and mitral valve prolapse also had tricuspid valve prolapse. The occurrence of this echocardiographic pattern as an isolated finding as well as associated with mitral valve prolapse was significantly less than previous angiographic reports. Patients with both these findings tended to be older than those with mitral valve prolapse alone, but clinically differed in no other way. Use of standardized technique can minimize errors in diagnosis.

Adolescent

Stabilization of the craniomandibular therapeutic relationship with etched porcelain bonded restorations: a clinical report.

The major advantage of this technique is sustaining the preexisting therapeutic position of the mandible during the restorative phase with minimal error in the occlusal scheme despite the type of restorative material. This clinical report demonstrated the conservative nature of bonding etched porcelain to tooth structure while concomitantly stabilizing the mandible to the maxillary dental arch.

Acid Etching, Dental

Utility of d4-PGE2 as an internal standard to quantify endogenous levels of PGE1, PGE2, 19OH PGE1 and 19OH PGE2 in human seminal fluid by GC-MS-SIM.

Four prostaglandins-PGE1, PGE2, 19OH PGE1 and 19OH PGE2-were quantified in human seminal fluid by GC-MS-SIM using only the internal standard, d4-PGE2. Methods and calculations were developed to minimize errors inherent in using only one internal standard for quantifying four closely related prostaglandins. Preliminary data concerning the statistical significance of the difference found between PGE and 19OH PGE levels in fertile, azospermic and oligospermic men are reported.

Chromatography, Gas

Validity of self-reported pregravid weight.

Self-reported pregravid weight is a commonly used baseline indicator of nutritional status in prenatal weight gain studies. This study assesses the validity of self-reported pregravid weight in 1591 gravidas who entered into prenatal care within the first trimester of pregnancy from 1986 to 1988 at the University of Maryland Medical Systems. A significant difference of 4.3 lb (t = 25.56, P < 0.001) was found between self-reported pregravid weight and estimated pregravid weight. Limits of agreement (interval within which 95% of the differences between the self-reported and measured weights) were constructed by population characteristics. Multiple linear regression models with estimated pregravid weight as the dependent variable were estimated by self-reported pregravid weight, body weight, height, age, race, education, insurance status, and marital status groups. A model with self-reported pregravid weight as the sole independent variable was found to explain 88% of the variance in estimated pregravid weight. Results of this study suggest that the validity of self-report pregravid weight varies with sociodemographic and anthropometric factors. Adjustment by a simple regression equation can minimize error in self-reported pregravid weight.

Adult

[A study of 11 ventilators for anesthesia: laboratory testing].

Eleven anaesthesia ventilators were instrumentally tested under various conditions. They included: Excel and Modulus II Plus (Ohmeda); 710 and Servo anaesthesia circle 985 (Siemens); Jollytronic (Soxil) and Elsa (Engström); SA2 and Cicero (Dräger); ABT 4,300 (Kontron); Monnal A and the prototype Alys (Taema). The test circuit comprised a two compartment model lung, a pneumotachograph, a pressure gauge in the "airway". The volume was calculated as the integral of flow rate. Each machine was calibrated by the firms' technicians. Before each test, the pneumotachograph was calibrated using a 11 air syringe and the pressure gauge with a 5 cm water column. Each machine ventilated the model lung for 30 min before starting the tests. There were five tests: 1) reliability of the machine's spirometer, 2) reliability of the ventilation rate, 3) reliability of pressure measurements, 4) effect of increasing fresh gas flow on spirometry, 5) effect of increasing downstream resistances. In usual simulated ventilatory conditions, all the machines accurately delivered the setted ventilation and spirometric measurements were with minimal error only. Several ventilators (SA2, Excel, 710, Elsa, ABT 4,300) did not succeed in maintaining their performances when compliance was strongly decreased or resistance of the test lung notably increased. Resistance in the circuit during simulated spontaneous ventilation was < 3.6 cmH2O.l-1.s-1. Increasing fresh gas flow raised the minute volume delivered in six ventilators. It is concluded that, during extreme ventilatory conditions, the inspired volume must be adjusted so as to maintain the inspired tidal volume. However, ventilators which increase inspiratory time in response to an increased mechanical load cannot be adjusted by this way.

Anesthesia, Closed-Circuit

Manufacture and utilization of antimony pH electrodes.

A new technique for manufacturing single-barreled and double-barreled antimony pH microelectrodes is described. The results of investigations into the accuracy of antimony as a pH sensor disclosed that the pH-voltage response is: 1) within the physiologic range, principally the result of the hydrogen ion activity of the solution in which the voltage is being developed, 2) in part, qualitatively anion-dependent, 3) modified by the presence of significant amounts of at least carbon dioxide, oxygen, and nitrogen gases, and 4) markedly offset by fluctuations in temperature. Our results further indicate that the accuracy of antimony as a pH sensor is determined by the quality of the calibration procedure. We conclude that if the antimony electrode is to accurately determine the pH of a biological fluid, the pH calibration solutions must closely resemble the unknown biological fluid with respect to temperature, PO2, PN2, and types of buffering anions. A calibration procedure is described which can minimize errors with antimony pH estimations when measuring the pH of proximal tubular fluid of the mammalian kidney.

Animals

Visual assessment of sporozoite and bloodmeal ELISA samples in malaria field studies.

The accuracy of visually assessing positivity for samples of field-collected Anopheles tested by enzyme-linked immunosorbent assays (ELISA) for Plasmodium falciparum sporozoites and human bloodmeals was determined during malaria field studies in Kenya. Six observers familiar with ELISAs evaluated 5,344 sporozoite ELISA samples and four observers evaluated 360 bloodmeal samples as either positive or negative based on the presence and strength of green-colored peroxidase reactions relative to controls on each microtiter plate. Interobserver agreement ranged from 97.9 to 99.8% for sporozoite samples and from 90.3 to 96.1% for bloodmeal samples. For both assays, the mean sensitivity and specificity of visual readings, compared with spectrophotometric readings, exceeded 98% when absorbance values were greater than or equal to 0.4 (on a scale of 0.0 to 2.0). Most incorrect visual readings occurred for samples with absorbance values between 0.2 and 0.4. The total percentage of samples classified correctly by visual examination ranged from 97.7 to 99.5% for the sporozoite ELISA and from 95.0 to 96.7% for the bloodmeal ELISA. Thus, there was minimal error associated with visually determining positive reactions for the ELISA assays used in malaria field studies.

Animals

A new guide for positioning of maxillary posterior denture teeth.

There is no definitive method for the arrangement of artificial teeth in complete denture construction. A new method is introduced whereby the maxillary posterior teeth have been set in approximate positions mediolaterally similar to their natural predecessors. The procedure is based on a constant relationship derived from the natural dentition. Its clinical application proved to be suitable for the arrangement of artificial teeth for complete dentures with minimal errors.

Adult

Studies on in vitro proteolytic sensitivity of peptides inhibiting herpes simplex virus ribonucleotide reductases lead to discovery of a stable and potent inhibitor.

The nonapeptide, HSV R2-(329-337), corresponding to the subunit 2 (R2) carboxyl terminus of herpes simplex virus (HSV) ribonucleotide reductases, specifically inhibits this enzyme activity. We report here that under standard reductase assay conditions, this peptide was rapidly degraded by proteases present in the partially purified enzyme extract. The main process of proteolysis involves the successive removal of Tyr329 and Ala330, which corresponds to an aminopeptidase activity. Determination of the proteolytic susceptibility of HSV R2-(329-337) analogs showed that natural modifications which are present in the homologous varicella zoster virus (VZV) nonapeptide decreased its susceptibility to protease action 1.5-fold. Nx-acetylation, a modification known to protect peptides against aminopeptidase attacks, greatly improved the proteolytic resistance of HSV and VZV nonapeptides. Moreover, Ac-VZV R2-(298-306) exhibited a 15-fold higher potency on reductase inhibition than HSV R2-(329-337). The degradation process of HSV R2-(329-337) was partially inhibited by amastatin, bestatin, and leupeptin whereas it was completely abolished by bacitracin, suggesting a combined action of more than one aminopeptidase activity. Moreover, bacitracin protected most of these nonapeptide analogs from proteolysis, although it was less effective in preventing HSV R2-(332-337) degradation. Our results indicate that it is possible to determine, in the presence of bacitracin, the relative inhibitory potencies of HSV R2-(329-337) analogs with minimal error due to proteolytic susceptibility. Moreover, HSV R2-(329-337) modifications that were found to protect the peptide against degradation might be useful to increase its efficacy in vivo.

Amino Acid Sequence

The temporal and steady-state relationships between activation of the sodium conductance and movement of the gating particles in the squid giant axon.

1. Comparisons were made between the kinetics and steady-state properties of the sodium conductance changes and of the sodium gating currents, in the squid giant axon perfused with caesium fluoride and maintained at a high membrane holding potential. The conductance measurements were made with reduced external sodium and as much electrical compensation as possible, in order to minimize errors caused by the series resistance. 2. After an initial delay of 10-150 musec whose size was a function of the holding potential and pulse amplitude, the conductance rise on depolarization followed cube law kinetics. 3. Values of the time constant taum, as defined by Hodgkin & Huxley (1952b), were determined for membrane potentials ranging between -140 and +70 mV. They lay on a nearly symmetrical bell-shaped curve with maximum (at 6-3 degrees C) of just under 500 musec at -36 mV. 4. Values of the gating current time constant tau(V) were determined over the same potential range, and found to lie on a very similar bell-shaped curve. A computed least-squares best fit gave the maximum as 460 musec, also falling at about -36 mV. 5. The midpoint of the minfinity curve lay at -34 mV, and its slope at this point was 0-0139 mV-1. Another series of measurements on intact axons gave a midpotential of -25 mV. In the perfused axons the state of the membrane was better described by the constant field equation than by gNa. Recalculation of minfinity from PNa shifted the curve about 15 mV in a positive direction.

Animals