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PubMed1989

Analysis of Ter-Ter enzyme kinetic mechanisms by computer simulation of isotope exchange at chemical equilibrium: development and application of ISOTER, a personal-computer-based program.

A convenient, personal-computer-based program has been developed that allows simulation of isotopic exchange kinetics at chemical equilibrium catalyzed by a three reactant-three product (TerTer) enzyme system: A + B + C integral of P + Q + R. This program, ISOTER, utilizes a rapid algebraic method to calculate the exchange rate between any reactant-product pair as a function of the substrate concentration and avoids altogether the necessity of deriving an explicit (but cumbersome and impractical) equation for exchange rate. ISOTER was used to generate model saturation patterns for 16 different TerTer kinetic mechanisms, varying different combinations of reactant-product pairs in constant ratio at equilibrium: [all substrates], [A, P], [B, Q], and [C, R], while holding the nonvaried components constant. These model studies indicate that virtually every one of these mechanisms can be distinguished from the others. In addition, ISOTER has been used to fit multiple sets of experimental data for Escherichia coli glutamine synthetase, which produced a set of rate constants consistent with the previously proposed "preferred order random" kinetic mechanism.

Computer Simulation↗
PubMed1991

N.m.r. and conformational analysis of the capsular polysaccharide from Streptococcus pneumoniae type 4.

The 1H- and 13C-n.m.r. data on the capsular polysaccharide (1) produced by Streptococcus pneumoniae type 4, the depyruvated polysaccharide (2), and a tetrasaccharide (3a) derived by Smith degradation of 2 were used as constraints on a computer-generated model of the conformation of 1 and to assess the effects of the pyruvic acetal substituent on the conformation. The dynamics of the polysaccharide systems and the influence of the pyruvic acetal were investigated using 13C-n.m.r. relaxation measurements.

Amides↗
PubMed1991

Ultraviolet photoreception in carp: microspectrophotometry and behaviorally determined action spectra.

This study demonstrates correlations between u.v. sensitivity and microspectrophotometric absorption spectra determined sequentially for the same group of individuals. We used the heart-rate conditioning technique to measure spectral sensitivity of carp, a species known to have u.v.-sensitive photoreceptors. Mean spectral sensitivity (n = 3) determined with a spectrally-broad background (450 nm long pass filter) revealed a small but consistent u.v. peak (lambda max of 380 nm) in addition to the other long wavelength peaks. An intense blue-green background (490 nm) produced a more prominent u.v. peak (lambda max of 400 nm) when a 450 nm longpass filter was added to the background. Microspectrophotometric measurements of u.v.-sensitive photoreceptors from one individual, which belonged to the group used in the spectral sensitivity experiments, revealed an average lambda max of 377.5 nm (SD +/- 4.5 nm, n = 5 cells). Bleaching and dichroic measurements of these receptors ensured that we were examining typical vertebrate visual pigments and not stable photoproducts. The mean spectral sensitivity points were compared with the u.v. and blue-sensitive visual pigment absorption spectra. A linear subtractive model and ocular media absorption were used in this comparison for the various photic conditions used in the heart-rate conditioning experiments. The model successfully described the sensitivity of the test fish in two cases but in a third case there was some discrepancy. The model generated curve was broader than the spectral sensitivity of the u.v.-sensitive cone mechanism on the shortwave side even though the ocular media corrections had been accounted for.

Animals↗
PubMed1988

Oxygen activation and ligand binding by pure heme-octapeptide microperoxidase-8 (MP-8).

The rapid, efficient preparation of pure microperoxidase-8 (MP-8) is described. Ligand binding studies confirm that MP-8 is monomeric in alkaline solution. It is shown that the monomeric MP-8 activates oxygen in a similar manner to that already reported for alkaline hemin, establishing the octapeptide as a possible second generation model for the oxygen activation/insertion reactions of the cytochrome P-450.

Animals↗
PubMedDate not supplied

Dipole source localization in the study of EP generators: a critique.

(1) The decision to solve the inverse problem in terms of one or more localized generators implies the assumption of a particular generator model. This assumption permits carrying out inverse dipole estimation. However, it is perilous to justify the procedure on the basis of the result. (2) Goodness of fit is a necessary but not sufficient criterion of model adequacy. A particular quantitative inverse solution has meaning only if it is accompanied by consideration of sensitivity to small changes in all of the free modeling parameters and estimates of perturbing factors including noise and forward calculation uncertainties.

Brain Mapping↗
PubMed1990

Gadolinium-DTPA-enhanced and digitally subtracted magnetic resonance imaging of estrogen-induced pituitary lesions in rats: correlation with pituitary anatomy.

Pituitary hypertrophy and tumors were induced in male Sprague Dawley rats using estradiol-17 beta. This tumor model generates a variety of pituitary lesions which are relevant to human pituitary disease. In order to characterize these lesions, gadolinium DTPA was injected intravenously into the tail vein of estrogen treated and control rats. High resolution T1-weighted MR images, pre- and postenhancement, were obtained at 8 different time points spanning 300 days following the subcutaneous implantation of the estrogen pellets. Images with 2-mm slice thickness were made with a 2 Telsa small-bore MR imaging system. Both normal and tumorous pituitaries were found to enhance with contrast agent, but contrast uptake was not uniform. Gd-DTPA distribution was sensitive to the different types of lesions generated in the course of this study. Digital subtraction of congruent images, pre- and postcontrast, provided difference images reflecting contrast concentration and allowed identification of subtle enhancement effects. Hypertrophic pituitaries displayed uptake of contrast, but the distribution of contrast agent was nonuniform and appeared mottled. A bright rim enhancement was often seen anterior to the pituitary gland, most likely arising from the oculomotor nerves and arachnoid. Histological slices in the same anatomical plane as the MR images were obtained on the animals allowing identification of individual lesions. Cystic areas within tumors were found to give strong contrast enhancement in less than five min postinjection. Solid and hemorrhagic areas of the pituitary tumor were hypo- to isointense relative to surrounding brain and did not take up contrast agent. Significant perfusion in these areas apparently does not occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Prediction of employability in schizophrenic patients.

This study, the third of a series of reports on employability and schizophrenia, investigated the effects of both interview and non-interview variables on employability. Data on 46 chronic schizophrenic inpatients included demographic and illness-related variables, measures of psychopathology and interview-based ratings of employment skill. Latent class analysis using linear structural relations (LISREL) modelling generated the main finding namely, that interview-based measures are the strongest determinants of employability. However, other variables pertaining to illness, prior functioning and negative symptoms, exert an effect on interview performance and hence indirectly influence employability ratings and judgements.

Activities of Daily Living↗
PubMed2026

Malnutrition and adverse outcomes after spine surgery: a systematic review and meta-analysis.

BACKGROUND CONTEXT: Malnutrition is linked to adverse surgical outcomes, but its impact in spine surgery remains unclear due to inconsistent findings and heterogeneous definitions, including use of serum albumin, prealbumin, lymphocyte count, the Geriatric Nutritional Risk Index, and the Prognostic Nutritional Index. We conducted a systematic review and meta-analysis to evaluate the relationship between malnutrition and postoperative outcomes in spine surgery. PURPOSE: To systematically evaluate the association between preoperative malnutrition and postoperative outcomes in patients undergoing spine surgery. STUDY DESIGN: Systematic review and meta-analysis. PATIENT SAMPLE: Patients undergoing elective or urgent spine surgery across included observational studies comparing malnourished vs well-nourished cohorts. OUTCOME MEASURES: Primary outcomes included postoperative mortality and overall surgical complications. Secondary outcomes included infectious complications (sepsis, urinary tract infection, wound complications), delirium, reoperation, 30-day and 90-day readmission, and prolonged length of hospital stay. METHODS: A systematic search of PubMed, Embase, Cochrane Library, and Web of Science was performed on April 7, 2025, following PRISMA guidelines. Studies directly comparing postoperative outcomes in malnourished vs well-nourished spine surgery patients were included. A random-effects model generated pooled odds ratios for complications. Outcomes assessed included mortality, surgical complications, infectious outcomes, readmission, reoperation, delirium, prolonged length of stay, and wound complications. RESULTS: Of 2,851 screened articles, 37 met the inclusion criteria, encompassing 16,987 malnourished patients. Malnutrition was associated with significantly increased odds of mortality (OR: 4.05, 95% CI [2.97-5.54]), delirium (OR: 3.95, 95% CI [2.49-6.27]), sepsis (OR: 2.77, 95% CI [2.31-3.33]), surgical complications (OR: 1.79, 95% CI [1.57-2.04]), urinary tract infection (OR: 1.81, 95% CI [1.59-2.06), wound complications (OR: 2.10, 95% CI [1.80-2.45]), reoperation (OR: 1.70, 95% CI [1.46-1.97]), prolonged length of hospital stay (OR: 3.46, 95% CI [2.57-4.65]), 30-day readmission (OR: 1.59, 95% CI [1.36-1.86]), and 90-day readmission (OR: 2.13, 95% CI [1.67-2.71]). CONCLUSIONS: Malnutrition was consistently associated with adverse outcomes after spine surgery. Routine nutritional assessment and targeted preoperative optimization should be considered a standard component of perioperative spine care to help reduce postoperative complications and improve recovery.

Humans↗
PubMed1990

High-dose, short-duration ribavirin aerosol therapy in children with suspected respiratory syncytial virus infection.

Nine children (aged 6 weeks to 7 years) with suspected respiratory syncytial virus infection received aerosal treatment with ribavirin, 60 mg/ml for 2-hour periods three times daily for up to 5 days. Five children received treatment via an endotracheal tube and four via an oxygen hood. Blood samples (3 to 17 per patient) and respiratory secretions (4 to 23 per patient) were assayed for ribavirin with reverse-phase high-performance liquid chromatography. Ribavirin triphosphate in erythrocytes was determined by ion-exchange high-performance liquid chromatography. The mean (+/- SD) peak ribavirin level after the first dose was 1725 +/- 2179 mumol/L in secretions and 3.8 +/- 2.6 mumol/L in plasma. Ribavirin in the secretions was rapidly cleared, with a mean (+/- SD), half-life of 1.9 +/- 0.8 hours. Plasma ribavirin increased with treatments to reach a steady state of 5 to 10 mumol/L. Mean peak ribavirin triphosphate levels were 15- to 300-fold higher than plasma ribavirin levels by the end of therapy. More than 98% reduction of viral load without the emergence of resistant virus was noted on day 3 of therapy. High-dose treatment was compatible with the aerosol equipment routinely used (small-particle aerosol generator, model 2-6000) for ribavirin administration and with ventilators. High-dose, short-duration ribavirin therapy was well tolerated by all patients, permitted easier accessibility for patient care, and may result in less environmental exposure of health care workers.

Administration, Inhalation↗
PubMed1986

Kinetic studies of reduction of a 1:1 cytochrome c-flavodoxin complex by free flavin semiquinones and rubredoxin.

The kinetics of reduction by free flavin semiquinones and reduced rubredoxin of the individual components of the 1:1 complex formed between horse heart cytochrome c and Clostridium pasteurianum flavodoxin have been studied. Complex formation did not affect the rate constant for reduction of flavodoxin by 5-deazariboflavin semiquinone, indicating that the accessibility of the flavin mononucleotide (FMN) of complexed flavodoxin is the same as in the free protein. Reduction of the complexed cytochrome c by the neutral flavin semiquinones of lumiflavin and riboflavin was significantly affected by complex formation (2-3-fold rate constant decrease), indicating that there are steric constraints on the accessibility of the cytochrome heme to small exogenous reductants. Reduction of complexed cytochrome c by the negatively charged semiquinones of FMN and Cl2FMN was also characterized. A repulsive electrostatic interaction between the reductants and complexed cytochrome was observed, whereas with free cytochrome an attractive interaction had previously been found. This is consistent with the presence of negative electrostatic potential at the protein interface due to uncompensated flavodoxin carboxylates, as predicted by Matthew et al. [Matthew, J. B., Weber, P. C., Salemme, F. R., & Richards, F. M. (1983) Nature (London) 301, 169-171]. Further, pseudo-first-order rate constants for the reduction of complexed cytochrome by these flavins had a nonlinear concentration dependence, rather than obeying simple second-order kinetics. This is interpreted by using a mechanism involving a rate-determining structural isomerization of the protein complex prior to the second-order electron-transfer step. The magnitude of the decrease in the rate constant for reduction of complexed cytochrome c by the negatively charged reduced rubredoxin was approximately the same as observed for free flavins. Furthermore, simple second-order kinetics were obtained, and the apparent electrostatic interaction between rubredoxin and the complex was attractive. These results suggest that flavodoxin was partially displaced from its complex with cytochrome c by a collisional interaction with rubredoxin. The effects of complexation on the kinetics have been correlated with a solvent-accessible surface representation of the computer-generated model of the flavodoxin-cytochrome c complex [Simondsen, R. P., Weber, P. C., Salemme, F. R., & Tollin, G. (1982) Biochemistry 21, 6366-6375]. The experimental observations are generally consistent with the structural model but clearly require the invocation of dynamic motions at the protein-protein interface.

Clostridium↗
PubMed2025

Insights into the Catalytic Activity of a Metagenome-Derived Urethanase.

The discovery of urethanases shows an opportunity to access the biotechnological recycling of polyurethane-based plastics (PURs), widely used in the manufacture of everyday materials. However, the mechanistic understanding of these enzymes remains under debate. In this work, we report a QM/MM-based mechanistic study of the metagenome-derived urethanase UMG-SP2 catalyzing the degradation of a urethane-like model compound, 4-nitrophenyl benzylcarbamate (pNC). A high-quality structural model generated with AlphaFold2, prior to the availability of the crystal structure, accurately captured the Ser-Ser-Lys catalytic triad characteristic of amidase signature enzymes. Highly accurate constant-pH nonequilibrium molecular dynamics and Monte Carlo (neMD/MC) simulations provided the full titration curve of active site Lys, explaining the need for alkaline media for the enzyme to be active. The generation of the free energy landscape, obtained by means of free energy perturbation methods with the M06-2X DFT functional describing the QM region of the full system, reveals an esterase-like three-step mechanism of UMG-SP2, i.e., acylation, hydrolysis, and decarboxylation, with all steps being kinetically feasible. Our computational results show very good agreement with experimental kinetic data, with a calculated free energy barrier of 21.2 kcal·mol-1 for the rate-determining step compared to 22.9 kcal·mol-1 derived from the experimentally measured turnover frequency (TOF). The present results also open the door for the final decarboxylation occurring in the solution after the release of the product of the hydrolysis step or within the active site. These findings provide an atomistic insight into the urethanase function and establish a robust framework for the future design of biocatalysts targeting polyurethane degradation.

Metagenome↗
PubMed2025

Vinigrol Tricyclic Scaffold Biosynthesis Employs an Atypical Terpene Cyclase and a Multipotent Cyclization Cascade.

Vinigrol (1) is a fungal diterpenoid consisting of a decahydro-1,5-butanonaphthalene ring system with no analogs in nature. Despite immense efforts in synthetic studies, the vinigrol biosynthesis pathway remains largely unknown. Herein, we identified a biosynthetic gene cluster for 1 and fully elucidated the biosynthetic pathway. By employing an AlphaFold-generated model structure, we identified the possible catalytic residues of the noncanonical terpene cyclase and analyzed their function by site-directed mutagenesis. We found that the G340A mutation opened a cryptic pathway for an unprecedented tetracyclic diterpene, defined here as virgarene. Retro-biosynthetic theoretical analysis provided a solid foundation for the complex cyclization pathway for the vinigrol scaffold, its chemical transformation to a structurally distinct bonnadiene, and redirection of the enzymatic cyclization cascade to virgarene. Close inspection of the terpene cyclization pathway via integrated experimental and theoretical approaches would allow efficient exploration of novel terpenoid chemistries.

Cyclization↗
PubMed1991

Sulfonylbenzoyl-nitrostyrenes: potential bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase.

The synthesis and biological activities of a series of sulfonylbenzoyl-nitrostyrene derivatives, a novel class of selective bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase, are described. The most potent derivatives inhibited the EGF-R tyrosine kinase, using angiotensin II as exogenous substrate, with IC50 values of less than or equal to 1 microM. No inhibition of the v-abl tyrosine kinase or the serine/threonine kinases PKC and PK-A was observed. In addition, active derivatives (compounds 5 and 12) effectively blocked the autophosphorylation of the EGF-R in vitro. Starting from the acids 5, 7, and 9, a series of esters, amides, and peptides was synthesized with the aim of increasing cellular penetration. Amides 14-18 showed potent antiproliferative effects using the EGF-dependent Balb/MK mouse epidermal keratinocyte cell line. Additionally, with the amide 14 inhibition of EGF-R autophosphorylation was demonstrated in the A431 cell line. CAMM studies using a computer-generated model for the transition state of the gamma-phosphoryl transfer from ATP to a tyrosine moiety and fitting experiments using the highly potent derivative 7 (IC50 value = 54 nM) support the hypothesis that the sulfonylbenzoyl group mimics a diphosphate moiety in the transition state. These results demonstrate that the rational design of tyrosine kinase inhibitors, using the inhibitory nitrostyrene moiety as a tyrosine mimic together with the sulfonylbenzoyl moiety as a diphosphate mimic, leads to highly potent and selective multisubstrate type inhibitors.

Angiotensin II↗
PubMed2026

Enhancing pan-cancer spatial transcriptomics at single-cell resolution with stPainter.

Subcellular spatial transcriptomics can resolve tissue architecture at cellular scale, but sparse gene panels and limited detection sensitivity constrain downstream analysis. Existing enhancement methods often require tissue-matched single-cell RNA sequencing (scRNA-seq) references and dataset-specific retraining. Here we show that stPainter, a conditional generative model pretrained on a pan-cancer scRNA-seq atlas, can enhance spatial transcriptomics data without matched references or retraining. Using a latent diffusion architecture guided by Stochastic Differential Equations (SDE), stPainter reconstructs expanded expression profiles from sparse measurements and produces latent representations for clustering and cell-state analysis. When we apply stPainter upon 6 spatial transcriptomics datasets of different cancer types, we demonstrate that our model empowers downstream biological analyses, including fine-grained subpopulation clustering and pathway enrichment. Comparison with spatially resolved proteomics (CODEX) provided independent support for regional agreement between imputed cellular compositions and protein-level tissue organization. These results establish stPainter as a scalable approach for analyzing tumor microenvironments without auxiliary sequencing data.

Spatial Transcriptomics↗
PubMed1992

Similarity between fluorescein-specific T-cell receptor and antibody in chemical details of antigen recognition.

A computer-generated model of the single-chain variable V alpha V beta fragment of the RFL3.8 T-cell receptor (TCR) specific for fluorescein served as a starting point for mutagenesis aimed at identification of its antigen-contacting residues. Selected backbone segments of the model representing regions of prominent sequence similarity between antibodies and TCRs were least-squares superimposed onto the corresponding segments of the crystallographically resolved 4-4-20 antibody complexed with its antigen, fluorescein. The superimposition placed the antibody-bound fluorescein molecule close to a cavity on the surface of the TCR model formed by the complementarity-determining region (CDR) loops. Some of the TCR cavity forming loops displayed sequence motifs related to canonical CDR loops previously found in antibodies. Six putative amino acid contacts were identified and single-chain TCRs with mutations at each of these positions were expressed in Escherichia coli, purified, refolded, and assayed for fluorescein binding. Five of the six mutations resulted in a loss of detectable binding. These RFL3.8 antigen combining site residues are distributed among the beta 3, alpha 1, and alpha 2 CDR loops and show striking chemical similarity to the known fluorescein contact residues on 4-4-20. Thus, antibodies and TCRs are similar both in their overall architecture and in the chemical details of specific antigen recognition.

Amino Acid Sequence↗
PubMed1992

Groove width and depth of B-DNA structures depend on local variation in slide.

The groove widths of DNA helix, especially minor groove width, are generally believed to be important for recognition of DNA by various types of ligands. It has been postulated earlier that large negative propeller twist, in the AT rich regions compresses the minor groove of duplex DNA. A systematic study has now been carried out by generating models with different values of local doublet and intra-basepair parameters and calculating their minor groove widths. It is found that several local doublet parameters affect the minor groove width but it depends most strongly on the local step parameters roll and slide when each parameter is considered individually. However, a detailed analysis of the various local parameters within the B-DNA family of crystal structures indicates that propeller twist and slide are most strongly correlated with the observed values of minor groove width. The groove depth is also strongly correlated with slide. Thus the local base sequence dependent variations in slide can modify both the groove width and depth and consequently determine the ligand binding properties of DNA.

Base Sequence↗
PubMed1990

Fractal geometry in mosaic organs: a new interpretation of mosaic pattern.

Fractal geometries have been widely observed in nature. The formulation of mathematical treatments of non-Euclidean geometry has generated models of highly complex natural phenomena. In the field of developmental biology, branching morphogenesis has been explained in terms of self-similar iterating branching rules that have done much toward explaining branch patterns observed in a range of real tissue. In solid viscera the problem is more complicated because there is no readily available marker of geometry in parenchymal tissue. Mosaic pattern provides such a marker. The patches observed in mosaic liver are shown to be fractal, indicating that the pattern may have arisen from a self-similar process (i.e., a process that creates an object in which small areas are representative of, although not necessarily identical to, the whole object). This observation offers a new analytical approach to the study of biologic structure in organogenesis.

Animals↗
PubMed1979

The discrete-time kinetic model analysis of DNA content distributions in experimental tumour cells.

A method was developed to analyse and characterize FMF measurements of DNA content distribution, utilizing the discrete time kinetic (DTK) model for cell kinetics analysis. The DTK model determines the time sequence of the cell age distribution during the proliferation of a tumor cell population and simulates the distribution pattern of the DNA content of cells in each age compartment of the cell cycle. The cells in one age compartment are distributed and spread into several compartments of the DNA content distribution to allow for different rates of DNA synthesis and instrument dispersion effects. It is assumed that the DNA content of cells in each age compartment has a Gaussian distribution. Thus, for a given cell age distribution the DNA content distribution depends on two parameters of the cells in each age compartment: the average DNA content and its coefficient of variation. As the DTK model generates the best fit DNA content distribution to the FMF measurement data, it enables one to estimate specific values of these two parameters in each stage of the cell cycle and to determine the fraction of cells in each cycle phase. The method was utilized to fit FMf measurements of DNA content distributions and to analyse their relationship tothe cell kinetic parameters, namely cell loss rate, cell cycle times and grwoth graction of exponentially growing Chinese hamster ovary cells in vitro and, also, with a wide range of coeffficients of variation, of the L1210 ascites tumour during the growth period.

Cell Cycle↗