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PubMed1975

Determination of the association constants and maximum binding capacities between estradiol and cytosol of the uterus by the least-squares analysis of the Scatchard plot.

The association constants and the binding capacities of association of small molecules with macromolecules have been determined by the tangent analysis, the graphical analysis, and the computer data analysis, by trial and convergence of the Scatchard plot. The analytical method for the calculation of the binding parameters based on the Scatchard plot was derived and the optimum values of the binding parameters were obtained by the least squares calculation based on the analytical method. The errors by the analytical method were smaller than those by the graphical method in the equilibrium system between 3H-estradiol and some cytosols of uterus.

Cytosol↗

PubMed1976

The temporal and periodic organization of REM eye movements in mental retardation.

Time trends and periodic cycles in REM sleep eye movements were examined in 6 functional and 6 mongoloid adolescent retardates. Both groups of subjects showed approximately equal percentages of linear trends, quadratic trends, linear and quadratic trends, and absence of trend. The eye movement time-series were subject to an orthogonal spectral analysis. In both groups of subjects, peak spectral estimates generally occurred at 10.6- or 21.3-min periods. Following this, the eye movements of the longest REM periods (and one long period of pre-sleep wakefulness) were subject to a least-squares spectral analysis. This analysis yielded estimates ranging from 22 to 44 min. Eye movements lacked the ultradian organization previously reported for eye movements of normal subjects. These results imply that the ultradian organization of REM sleep and the ultradian organization of eye movements may be independent.

Adolescent↗

PubMed1979

Differential potentiometric method for determining dissociation constants of very slightly water-soluble drugs applied to the sulfonamide diuretic chlorthalidone.

A renewed application of potentiometric acid-base titrations is described, by which dissociation constants of practically water-insoluble drugs can be measured accurately. The method uses the difference in the amount of titrant between a suitable aqueous solvent and a solution of the drug in that solvent. Such potentiometric difference titrations were conducted on a 3.7 X 10(-4) M solution of chlorthalidone in 0.1 M aqueous KCl in the pH 3.5--10.6 range at 25 degrees. Nonlinear least-squares regression analysis was applied to the data. From four determinations, a value of 9.24 +/- 0.02 (mean +/- SEM) resulted for the apparent dissociation constant of the first chlorthalidone acid group. The thermodynamic dissociation constant was calculated at pKa1 = 9.35 (25 degrees) by using a correction for activity.

Chlorthalidone↗

PubMed2025

PLSKO: a robust knockoff generator to control false discovery rate in omics variable selection.

MOTIVATION: Integrating the knockoff framework with any variable-selection method delivers stringent false discovery rate (FDR) control without recourse to p-values, offering a powerful alternative for differential expression analysis of high-throughput omics datasets. However, existing knockoff generators rely on restrictive modelling assumptions or coarse approximations that often inflate the FDR when applied to real-world data. RESULTS: We introduce Partial Least Squares Knockoff (PLSKO), an efficient, assumption-free generator that remains robust across diverse omics platforms. Our extensive simulations show that PLSKO is the only method to maintain FDR control with sufficient power in complex non-linear settings. Our semi-simulation studies drawn from RNA-seq, proteomics, metabolomics, and microbiome experiments confirm PLSKO generates valid knockoff variables. In pre-eclampsia multi-omics case studies, we combine PLSKO with Aggregation Knockoff to address the randomness of knockoffs and improve power, and demonstrate the method's ability to recover biologically meaningful features. AVAILABILITY AND IMPLEMENTATION: Our proposed algorithm is available on Github (https://github.com/guannan-yang/PLSKO) and Zenodo (https://doi.org/10.5281/zenodo.16879594).

Algorithms↗

PubMed2026

Fate of antibiotic resistance genes during rural domestic wastewater treatment: Anaerobic unit as enrichment hotspot versus aerobic unit as attenuation zone.

Rural domestic wastewater treatment systems are important but understudied reservoirs for antibiotic resistance genes (ARGs), whose full-process migration mechanisms remain unclear. Herein, the contribution of each treatment unit of ARGs was investigated using metagenomic methods across two seasons in typical rural domestic wastewater treatment systems. Although a removal efficiency (69 % in winter and 22 % in summer) was observed for ARGs, higher antibiotic residues and temperature dramatically induced ARG occurrence in wastewater and horizontal gene transfer (HGT) risk during wastewater treatment. The ARG abundances in the anaerobic unit increased by 1.6-2.1 fold compared to the regulating pool, primarily driven by elevated mobile genetic element (MGE) activity. In sharp contrast, ARG reduction was achieved through ARG host removal and suppressed HGT potential in the aerobic unit. Notably, mobile ARGs were dominated by tetracycline resistance genes in winter and co-dominated by tetracycline and sulfonamide genes in summer, with most flanked by transposases. Key pathogenic hosts, including Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa carrying ARG-MGE complexes, were primarily concentrated in the regulating pool and the influent, forming high-risk upstream sources of dissemination. Partial least-squares path model highlighted MGEs as the primary drivers, and variance partitioning analysis indicated that MGEs account for 31 % of the explained variation in ARGs during wastewater treatment. In summary, the anaerobic unit was an ARG enrichment hotspot, while the aerobic unit as ARG attenuation zone during wastewater treatment. These findings provide crucial evidence to optimize rural wastewater treatment processes and to target the control of antibiotic resistance.

Wastewater↗

PubMed1976

Application of a spectrophotometric method to the determination of the composition of oligonucleotides obtained from cysteine transfer ribonucleic acid.

1. The applications of methods for determining the composition of oligonucleotides from u.v.-absorption spectra is described. 2. In the first method absorbances at selected wave-lengths were read from the spectra of oligonucleotides in solution in 7 M-urea which had been recorded at acid and alkaline pH values. 3. In the second method absorbances were sampled automatically at regular time-intervals during scans at acid and alkaline pH of each spectrum, converted into digital signals and recorded on paper take for computer processing. The holmium spectrum in the region of the holmium peak at 333.7 nm was superimposed on each nucleotide spectrum. The position of this peak maximum was used as a standard reference point in the computer-based analysis. 4. By using either method the composition was calculated by a least-squares procedure by using a library of values for five standard nucelotides obtained in a similar manner. 5. The methods gave satisfactory compositions for mixtures of mononucleotides as well as for five dinucleoside monophosphates. 6. Methods of minimizing the effects on the nucleotide composition of spectural changes due to base stacking are discussed. 7. The compositions of some oligonucleotides obtained during an investigation of the nucleotide sequence of tRNA (Cys) were determined and agreed with the sequences found by other methods.

Base Sequence↗

PubMed2026

Effect of long-term sepiapterin treatment on dietary phenylalanine tolerance in patients with phenylketonuria: Interim results from the phase 3 APHENITY Extension Study.

PURPOSE: To report interim results from the ongoing, open-label, phase 3 APHENITY Extension Study (NCT05166161), evaluating long-term treatment with sepiapterin in patients with phenylketonuria. METHODS: Participants received an age-based dose of oral sepiapterin daily; those with mean blood phenylalanine (Phe) levels <360 μmol/L (<5.95 mg/dL) after 2 weeks underwent a 26-week dietary Phe tolerance assessment, wherein dietary Phe intake was adjusted and blood Phe levels monitored. Other participants continued treatment with optional diet liberalization. Primary endpoints included change from baseline to week 26 in dietary Phe intake and treatment-emergent adverse events (TEAEs). RESULTS: As of September 2, 2024, 169 participants received sepiapterin (median [minimum, maximum] age: 14.0 [0.2, 55.0] years, median exposure: 72.9 weeks); 102 participants underwent dietary Phe tolerance assessments. Mean (SD) dietary Phe intake increased from 27.6 (18.0) mg/kg/day at baseline to 62.5 (41.5) mg/kg/day at week 26 (least-squares mean change [SE]: 36.4 [2.8] mg/kg/day from baseline) (P < .0001 from post hoc analysis). The incidence of treatment-related TEAEs was 29.0%; 3 participants (1.8%) discontinued treatment owing to treatment-related TEAEs. There were no treatment-related serious TEAEs or deaths. CONCLUSION: Interim results support the long-term safety of sepiapterin and demonstrate the potential for diet liberalization in adults and children with phenylketonuria. GOV IDENTIFIER: NCT05166161 (https://www. CLINICALTRIALS: gov/study/NCT05166161; date of registration, December 8, 2021).

Humans↗

PubMed1976

Statistical characterization of the random errors in the radioimmunoassay dose--response variable.

We have developed practical methods for evaluating the magnitude of the random errors in radioimmunoassay dose--response variables, and the relationship between this error and position on the dose--response curve. This is important: to obtain appropriate weights for each point on the dose--response curve when utilizing least-squares curve-fitting methods; to evaluate whether the standards and the unknowns are subject to error of the same magnitude; for quality-control purposes; and to study the sources of errors in radioimmunoassay. Both standards and unknowns in radioimmunoassays for cAMP and cGMP were analyzed in triplicate. The same mean (Y), sample standard deviation, sy, and variance (2-y) of the response variable were calculated for each dose level. The relationship between s 2-y and y was calculated utilizing several models. Results for standards and unknowns from several assays were pooled, and a curve smoothing procedure was used to minimize random sampling errors. This pooling increased the reliability of the analysis, and confirmed the presence of the theoretically predicted nonuniformity of variance. Thus, the calculation of results from these radioimmunoassays should utilize a weighted least-squares curve-fitting program. These analyses have been computerized, and can be used as a "pre-processor" for programs for routine analysis of results of radioimmunoassay.

Analysis of Variance↗

PubMed1976

Analysis of the electron paramagnetic resonance spectrum of the cobalamin intermediate in ribonucleotide reduction.

EPR absorption-derivative lineshapes have been computed and least-squares fitted to the spectrum of the intermediate derived from 5'-deoxy-5'-adenosylcobalamin in the ribonucleotide reductase reaction. A Gaussian-type intrinsic lineshape was assumed and the effects of inhomogenous broadening, rotation of coordinate axes of the A-tensor relative to the g-tensor, angular dependence of transition probability and ligand hyperfine splitting have also been investigated. When the overall spectrum was computed as the sum of the lineshapes corresponding to two distinct Co(II) species, A and B, each having rhombic symmetry, the least squares procedure converged to a much better fit than with a single species, and matched almost all of the features of the experimental spectrum. The magnetic properties of A and B were compared with those of a series of other Co(II) complexes by a plot of g - g versus A - A. The results eliminate cobalt with 5-coordination to nitrogen for A and B, and suggest low-spin cobalt complexes having strongly distorted 6-fold coordination. The possibility that the sixth, symmetry-decreasing ligand is the oxygen molecule is excluded by the chemistry of the system and by the EPR properties of previously reported cob(II)alamins. It is suggested that the sixth ligand is a carbonyl, amide or sulfhydryl group of an enzyme sidechain which is inserted off-axis into the coordination position so as to exert the observed symmetry-lowering effect.

Binding Sites↗

PubMed1978

The emission yields of delayed and prompt fluorescence from chloroplasts.

1. The decay of delayed fluorescence from chloroplasts blocked with 3-(3,4-dichlorophenyl)-1,1-dimethylurea and uncoupled with gramicidin has been measured in the time range 0.75--45 ms by use of a laser phosphoroscope. 2. The decays have been analysed as the sum of three first-order components of approximate half-lives 0.2, 2.5 and 300 ms by a computer-assisted least-squares fit procedure. 3. The prompt fluorescence yield of the chloroplasts was manipulated by changing the cation concentration of the chloroplast-suspending medium. 4. Analysis of the concentration dependence of the components of the delayed fluorescence decay and of the prompt fluorescence inductions indicates that the emission yield of the intermediate (tau approximately 2.5 ms) component of the decay is equal to the fluorescence yield of a Photosystem II photosynthetic unit with an open trap, and that for the slow (tau approximately 300 ms) component the emission yield is equal to the total Photosystem II prompt fluorescence yield. 5. It is concluded that the delayed fluorescence yield in the time range studied is a complex function of time, which may be due to there being different mechanisms leading to delayed fluorescence production at short and long times after cessation of illumination.

Chloroplasts↗

PubMedDate not supplied

X-ray-diffraction study and determination of absolute configuration of the anticancer drug S(--)cyclophosphamide (Endoxan, Cytoxan, NSC-26271).

(--)Cyclophosphamide(1) crystallized from tetrachloromethane in the triclinic space group P1 with cell dimensions a = 10.500 (4) A, b = 10.490 (4) A, c = 10.761 (4) A, alpha = 110.0 (2) degrees, beta = 110.0 (2) degrees, gamma = 108.9 (2) degrees. Three molecules are contained in the unit cell. The X-ray analysis was based on diffractometer measurement of 2635 independent reflections and the structure was solved by Patterson and direct methods. The final R and Rw factors after full-matrix least-squares refinement are 0.0717 and 0.0677, respectively. The absolute configuration is S based on Hamilton's R-factor ratio test. The oxazaphosphorinane ring exists in a chair form with the bis-beta chloroethyl-amino group in equatorial position and about perpendicular to and bisecting the O--P--N plane. The structure is similar to that found in racemic 1 except a different conformation about one ethyl-amino N--C bond.

Cyclophosphamide↗

PubMed2026

Phase 3 Trial of Oral Infigratinib in Children with Achondroplasia.

BACKGROUND: Achondroplasia is a genetic skeletal condition caused by FGFR3 pathogenic variants. Infigratinib, an oral FGFR1-3 tyrosine kinase inhibitor, down-regulates key pathways in the pathogenesis of achondroplasia. METHODS: In this phase 3, multicenter, double-blind, placebo-controlled trial, we randomly assigned children with achondroplasia (3 to 17 years of age) in a 2:1 ratio to receive infigratinib (at a dose of 0.25 mg per kilogram of body weight) or placebo once daily for 52 weeks. The primary end point was the change from baseline in the annualized height velocity in the infigratinib group as compared with the placebo group at week 52. Key secondary end points were the change from baseline in the height z score and in the upper-to-lower body segment ratio at week 52. The primary analysis evaluated the treatment effect at week 52 in the full analysis population, with missing data handled with a prespecified imputation approach. RESULTS: In all, 114 patients underwent randomization: 75 patients to receive infigratinib (with 1 withdrawal before treatment) and 39 patients to receive placebo. The difference between infigratinib and placebo in the least-squares mean change from baseline to week 52 was 1.74 cm per year (95% confidence interval [CI], 1.31 to 2.17; P<0.001) for the annualized height velocity, 0.32 (96% CI, 0.23 to 0.41; P<0.001) for the height z score, and -0.02 (96% CI, -0.06 to 0.01) for the upper-to-lower body segment ratio. Adverse events occurred in 71 of 74 patients (96%) in the infigratinib group and in 37 of 39 patients (95%) in the placebo group; serious adverse events occurred in 4 of 74 patients (5%) and 1 of 39 patients (3%), respectively. No serious adverse events or adverse events leading to treatment discontinuation were considered by the investigator to be related to infigratinib or placebo. CONCLUSIONS: In children with achondroplasia, treatment with once-daily oral infigratinib for 52 weeks resulted in a significantly greater increase from baseline in the annualized height velocity than placebo. (Funded by BridgeBio Pharma; PROPEL 3 ClinicalTrials.gov number, NCT06164951; EudraCT number, 2023-506130-67.).

Adolescent↗

PubMed1975

Partial pharmacodynamic model for the circadian-episodic secretion of cortisol in man.

A pharmacodynamic model was developed to facilitate computer analysis of the circadian-episodic influx of cortisol into plasma from the adrenal gland. The model consists of a catenary system of a biorhythmic control, the adrenal gland, and a body compartment containing circulating cortisol. Computer nonlinear regression analysis was carried out on data consisting of plasma cortisol concentrations measured at 30-min intervals over 1 day in a group of normal children. Circadian rhythmic synthesis of cortisol by the adrenal gland was described by a sinusoidal function which provides the level (284 plus or minus 50 mugg/h/m2) and amplitude (245 plus or minus 50 mug/h/m2) of the synthesis rate and the period (24 hours) and acrophase (8.14 plus or minus 1.95 h) of the cycle. Cosinor analysis of the data confirmed a highly significant circadian rhythm in the daily synthesis rate of cortisol. Episodic secretion, described by an empirical switch function, is assumed to result from accumulation of small amounts of cortisol precursors in the adrenal gland and intermittent stimulation of cortisol release by ACTH. This was found to take place over 46.6 plus or minus 2.4% of a 24-h day. Circulating cortisol is contained in a single body compartment with an apparent volume of distribution (5.3 plus or minus 0.55 liters/m2) from which elimination occurs by first-order metabolic clearance. The biological half-life averaged 0.96 plus or minus 0.18 h. Upon least-square optimization of selected kinetic parameters, the circadian-episodic model increases the accountable variation (r2 x 100) to 89% in comparison with the 35% obtained by use of only a periodic function.

Adrenal Glands↗

PubMed1976

Changes in the electric dipole vector of human serum albumin due to complexing with fatty acids.

The magnitude of the electric dipole vector of human serum albumin, as measured by the dielectric increment of the isoionic solution, is found to be a sensitive, monotonic indicator of the number of moles (up to at least 5) of long chain fatty acid complexed. The sensitivity is about three times as great as it is in bovine albumin. New methods of analysis of the frequency dispersion of the dielectric constant were developed to ascertain if molecular shape changes also accompany the complexing with fatty acid. Direct two-component rotary diffusion constant analysis is found to be too strongly affected by cross modulation between small systematic errors and physically significant data components to be a reliable measure of structural modification. Multicomponent relaxation profiles are more useful as recognition patterns for structural comparisons, but the equations involved are ill-conditioned and solutions based on standard least-squares regression contain mathematical artifacts which mask the physically significant spectrum. By constraining the solution to non-negative coefficients, the magnitude of the artifacts is reduced to well below the magnitudes of the spectral components. Profiles calculated in this way show no evidence of significant dipole direction or molecular shape change as the albumin is complexed with 1 mol of fatty acid. In these experiments albumin was defatted by incubation with adipose tissue at physiological pH, which avoids passing the protein through the pH of the N-F transition usually required in defatting. Addition of fatty acid from soluion in small amounts of ethanol appears to form a complex indistinguishable from the "native" complex.

Binding Sites↗

PubMed2026

Quality of life with palbociclib plus tamoxifen in hormone receptor-positive, HER2-negative advanced breast cancer: results from PATHWAY, an Asian international, double-blind, randomized phase 3 trial.

BACKGROUND: In the Asian international PATHWAY trial, palbociclib-tamoxifen demonstrated improved progression-free survival compared with placebo-tamoxifen in patients with HR+/HER2- locally advanced or metastatic breast cancer (ABC). This analysis compared quality of life (QoL) between treatment arms. METHODS: Pre/peri or postmenopausal women with HR+/HER2- ABC were randomly assigned 1:1 to receive palbociclib-tamoxifen or placebo-tamoxifen. Patient-reported outcomes were assessed on day 1 of cycles 1 (baseline), 4, and 7, and at the end of treatment (EOT) using the EORTC QLQ-C30 and QLQ-BR23 questionnaires. Least-square mean (LSM) changes in scores from baseline were calculated. Kaplan-Meier method was used to calculate time to deterioration (TTD) in the minimally important difference (MID) in the pain subscale. RESULTS: In the comparison between treatment arms, no significant differences were observed in LSM changes in scores from baseline in global QoL (cycle 4: 0.70 [95% confidence interval (CI): -5.00, 6.41]; cycle 7: 2.17 [95% CI: -4.14, 8.48]; EOT: -5.19 [95% CI: -11.64, 1.26]). For both the EORTC QLQ-C30 and QLQ-BR23 functional and symptom subscales, no clinically meaningful differences between treatment arms were found in the LSM changes in scores from baseline. Median TTD in the MID in the pain subscale was 32.5 months (95% CI: 11.7, not estimable) for the palbociclib-tamoxifen arm and 21.2 months (95% CI: 5.5, 43.5) for the placebo-tamoxifen arm (hazard ratio = 0.729 [95% CI: 0.467, 1.138]). CONCLUSIONS: The combination of palbociclib and tamoxifen delayed deterioration in patients' QoL while they experienced reduced risk for disease progression. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03423199; study registration date: February 6, 2018.

Humans↗

PubMed1976

A mathematical analysis of the substrate effect observed in 3beta-hydroxysteroid dehydrogenase reactions of rat testicular microsomes.

The substrate effect in enzyme reactions has been explained mostly in terms of an additional substrate binding site on the enzyme other than the catalytic site. A rate equation for the reaction is introduced according to the steady state mechanism as follows: v = (Ps3+Qs2+Rs)/(s3+Ls2+Ms+N), were the six parameters, L,M,N,P,Q, and R, can be determined by the least-squares method from the experimental points. The v vs. s curve has an asymptote parallel to the s abscissa, and can be classified into one of four types. The type A curve has an intersection with the asymptote and an apparent maximum velocity; the curve descends toward the asymptote. Type B has no intersection and no stationary point; the curve ascends toward the asymptote. Type C has two intersections and two stationary points, an apparent maximum velocity and a minimum velocity; the curve ascends toward the asymptote. Type D has no intersection and two stationary points; the curve ascends toward the asymptote. The equation was applied to the 3beta-hydroxysteroid dehydrogenase [EC 1.1.1.145] reaction of rat testicular microsomes. The conversion of 3beta-hydroxyandrost-5-ene-17-one was represented by type C, with an apparent maximum velocity of 0.338 nmole/min/mg protein at 0.912 muM of the substrate concentration, minimum velocity of 0.108 nmole/min at 16.6 muM, and saturating velocity of 0.169 nmole/min at infinite concentration of the substrate. The converson of 3beta-hydroxypregn-5-ene-20-one was of type B, having two inflexion points, 0.320 nmole/min at 2.735 muM and 0.814 nmole/min at 12.39 muM, and a saturating velocity of 3.80 nmoles/min at infinite concentration of the substrate.

Animals↗

PubMed1978

Autoxidation of native oxymyoglobin. Kinetic analysis of the pH profile.

The rate of autoxidation of native oxymyoglobin to metmyoglobin has been examined over the pH range of 4.8--12.6 in 0.1 M buffer at 25 degrees C, and some 40 values of the observed first-order rate constant, kobs, are plotted against pH of the solution. In order to understand the kobs--pH profile thus obtained, some mechanistic models are proposed for the autoxidation reaction. The fitting of their rate equations as a function of pH has been examined to the experimental kobs-pH plot by a least-squares method with the use of a digital computer. The complicated pH-profile can be best explained by the 'acid-base catalyzed three states model', which reveals not only the catalytic role of hydrogen ions and hydroxyl ions, but also the involvement of two dissociation groups of myoglobin molecule in the autoxidation reaction.

Animals↗

PubMed1979

Effects of D and L amino acid residues in linear peptides on carbon-13 nuclear magnetic resonance parameters.

The 13C spectra of the linear tripeptidyl diastereoisomers, Gly-Gly-Leu, Gly-Gly-D-Leu, Leu-Gly-Gly, D-Leu-Gly-Gly, Ala3, Ala-Ala-D-Ala, Ala-D-Ala-Ala, Val3, and Val-Val-D-Val are very similar or even identical at pH meter readings of 1.0, 7.0 and 12.0 in D2O. The spectra of Pro-Leu-Gly-NH2 and Pro-D-Leu-Gly-NH2 likewise show only minor differences in 13C chemical shifts (less than 0.4 p.p.m.) under similar conditions. This contrasts significantly with previous findings comparing 13C chemical shifts of cyclo(Pro-Leu) and cyclo(Pro-D-Leu) where major differences in chemical shifts were observed for both residues due to differences in conformational constraints present in these cyclic proline-containing peptides. The least-squares fit of spin-lattice relaxation times (T1) for Pro-Leu-Gly-NH2 and Pro-D-Leu-Gly-NH2 show that it is not possible to fit all the T1 values to a unique and rigid structure whether folded or extended. The glycyl residue undergoes enhanced motion when compared with the prolyl and leucyl residues. Internal motion must be postulated within the proline ring and for the CH3 groups of leucine.

Amino Acid Sequence↗