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PubMed1994

The 47-kDa major lipoprotein immunogen of Treponema pallidum is a penicillin-binding protein with carboxypeptidase activity.

The recent model of Treponema pallidum molecular architecture proposes that the vast majority of the bacterium's integral membrane proteins are lipoprotein immunogens anchored in the cytoplasmic membrane while the outer membrane contains only a limited number of surface-exposed transmembrane proteins. This unique model explains, in part, the organism's remarkable ability to evade host immune defenses and establish persistent infection. Our strategy for refining this model involves demonstrating that the physiological functions of treponemal membrane proteins are consistent with their proposed cellular locations. In this study, we used an ampicillin-digoxigenin conjugate to demonstrate by chemiluminescence that the 47-kDa lipoprotein immunogen of T. pallidum (Tpp47) is a penicillin-binding protein. Reexamination of the Tpp47 primary sequence revealed the three amino acid motifs characteristic of penicillin-binding proteins. A recombinant, nonlipidated, soluble form of Tpp47 was used to demonstrate that Tpp47 is a zinc-dependent carboxypeptidase. Escherichia coli expressing Tpp47 was characterized by cell wall abnormalities consistent with altered peptidoglycan biosynthesis. Though the inability to cultivate T. pallidum in vitro and the lack of genetic exchange systems continue to impede treponemal research, this study advances strategies for utilizing E. coli molecular genetics as a means of elucidating the complex relationships between syphilis pathogenesis and T. pallidum membrane biology.

Amino Acid Sequence↗

PubMed1992

Elevated serum enzyme activity: an explanation-based model.

The well-documented pattern of elevated serum enzyme activity (ESEA) data after a single bout of unaccustomed exercise can very easily be modeled using a biexponential curve. However, the changed pattern of ESEA after a second exercise bout, or after a period of conditioning or during repetitive training, demonstrates that exercise-induced adaptations have been taking place. The mechanism for this is unclear. One plausible explanatory hypothesis is that within the pool of muscle fibers, some fibers are stress susceptible or weak, and the pool becomes diminished as a result of damage induced by earlier exercise. Repair of the muscle damage takes place during the period after exercise but may be incomplete at the time of a subsequent exercise bout, in which case ESEA amplitude is reduced. Frequently repeated bouts may lead to chronic ESEA. These ideas are developed, both mathematically and graphically, by means of a compartment model approach. In so doing, the model explains documented patterns of ESEA response to single and multiple exercise bouts, both closely and widely spaced. Predictions are possible using the model, in particular the previously unreported baseline overshoot (reduction below resting levels) in serum enzyme activity occurring beyond 82 h after very severe exercise. Some directions for experimentation to test the validity of the model are suggested.

Creatine Kinase↗

PubMed1994

[Is in depth diagnosis important in renal artery stenosis?].

The experimental discovery of the pathophysiological relationship between renal artery stenosis and arterial hypertension was historically reported (1934) before the clinical description of the disease in human patients (1950). The experimental model explains the relation between renal ischemia, renal endocrine activation, and morphological alterations of the homo and contralateral kidneys. In particular, the experimental model improves the understanding of the evolution of renovascular disease. In human patients, renal artery stenosis does not always lead to clinical disease. Because of the frequency of arterial hypertension, there is not always a clear relationship between hypertension and renal insufficiency or renal artery stenosis. Therefore a complete diagnosis of renal endocrine and exocrine function is needed to understand this relation before deciding on the therapeutic approach. This diagnosis is made by exploration of the renal renin-angiotensin axis, its pharmacological blockade and the response of the excretory function. This approach corresponds to the clinical description of the evolution of the disease; the peripheral and renal vein renin assays; the pressure and scintigraphic response to converting enzyme inhibition and renal morphological definition by echography and CT scan. This pathological approach permits a rational choice of the therapeutic indication: non-intervention, specific medical treatment, endovascular or surgical revascularization or nephrectomy.

Animals↗

PubMed2026

Dual β-lactam therapy against high-risk Pseudomonas aeruginosa isolates: a dynamic in-vitro infection model study integrating population genomics with quantitative systems pharmacology modelling and simulations.

BACKGROUND: Pseudomonas aeruginosa has an extraordinary capacity for resistance emergence during treatment, even with newer antipseudomonals. There is a gap in understanding how resistance mechanisms affect the time-course of bacterial response to these newer agents. Traditional approaches for predicting pathogen response to an antibiotic do not apply to combination therapy. We aimed to develop a modelling framework to predict treatment response based on resistome information, using isolates of the worldwide-disseminated high-risk clone sequence type (ST) 235 and β-lactam antibiotics as the example. METHODS: In this hollow-fibre in-vitro infection study, we used three extensively drug-resistant ST235 clinical isolates from the national collection of the Clinical Microbiology Department of the Hospital Son Espases (Palma de Mallorca, Spain) that were hospital-acquired, were isolated following routine microbiological procedures from different patients between 2017 and 2022, were susceptible to ceftolozane-tazobactam, and had different levels of meropenem resistance. The selected isolates (ST235-05, ST235-09, and ST235-10) showed classical β-lactam resistance mechanisms pre-treatment. The isolates were investigated in 240-h dynamic hollow-fibre in-vitro infection models (HFIMs). The studies exposed the isolates to pharmacokinetic profiles of ceftolozane-tazobactam (simulating 1 g of ceftolozane and 0·5 g of tazobactam as a 3-h infusion every 8 h) and meropenem (simulating 6 g per day continuous infusion) as observed in hospitalised patients, as monotherapy and in combination. Treatment response was assessed through the quantification of the time-courses of viable total and resistant bacteria. Whole-genome sequencing identified the mechanisms of emerging resistance. A quantitative systems pharmacology (QSP) approach was used to model total and resistant bacterial counts and corresponding pharmacokinetic data from the HFIM. Monte Carlo simulations were used to predict treatment responses in 1000 virtual infected patients treated with ceftolozane-tazobactam and meropenem as monotherapies or in combination over 10 days. FINDINGS: In the HFIMs, each antibiotic alone amplified resistance by approximately 48 h for all isolates; that is, monotherapies resulted in a higher concentration of resistant bacteria compared with the control treatment at the respective time, except ceftolozane-tazobactam against ST235-10. Combination of ceftolozane-tazobactam and meropenem was synergistic (bacterial counts ≥2 log10 colony forming units [CFU] per mL lower than the best performing monotherapy and initial inoculum) against all isolates and suppressed resistance. Against ST235-10, ceftolozane-tazobactam monotherapy reduced counts to less than 1 log10 CFU per mL from 192 h onwards, whereas the combination reached less than 1 log10 CFU per mL by 24 h. Across strains, population genomics confirmed monotherapy failures were associated with emerging resistance mechanisms (ceftolozane-tazobactam: ampC Ω-loop mutations; meropenem: ftsl mutation). The developed QSP model incorporated baseline resistance mechanisms and those emerging in resistant mutant subpopulations. The model explained and predicted the monotherapy failures involving amplification of these subpopulations, and synergistic killing and resistance suppression by the combination. Simulations using the model predicted bacterial regrowth above the initial inoculum for more than 90% of patients after 0 to approximately 3 days for meropenem monotherapy across all strains and for ceftolozane-tazobactam monotherapy against ST235-05 and ST235-09. For ceftolozane-tazobactam monotherapy against ST235-10, regrowth was predicted for approximately 30% of patients. In contrast, the simulations predicted sustained bacterial killing of at least 2 log10 CFU per mL compared with the initial inoculum by the combination for more than 89% of patients across all strains. INTERPRETATION: To our knowledge, this model is the first to characterise and predict the time-course of responses of clinical isolates to antibiotics only by the resistance mechanisms present and their complex interplay, representing a step towards pathogen-specific, personalised medicine. FUNDING: Australian National Health and Medical Research Council.

Pseudomonas aeruginosa↗

PubMed2005

Discrepancies between vertebral bone density values: the least dense vertebra.

Vertebral bone mineral density (BMD) measurements by DXA are considered reliable indicators of local fracture risk in the absence of radiographic deformities. The clinical evaluation of one individual vertebra presenting a BMD value significantly less than the others is attempted in this study. For a period of 30 months, BMD measurements of L1-L4 vertebrae and femoral neck (FN) were performed by DXA in 817 postmenopausal women, aged under 65 years, with a BMI less than 33 kg/m(2). In 204 (25%) of these women (group A), the least dense vertebra (LDV) presented a BMD value lower than 92.4% from the immediate denser vertebra. The remaining 613 women comprised group B. Women with X-ray proven vertebral degenerative lesions or deformities were excluded from the study. Among the four measured vertebrae, L1 was the most frequent LDV (47%), whilst L3 was the most rare (2%). Absolute and age-adjusted BMD values of L1-L4 and FN, as well as the proportions of osteopenic or osteoporotic women, did not differ significantly between the two groups. A significant positive correlation was observed between either L1-L4 or LDV and FN BMD values in both groups, but stepwise multiple regression analysis revealed that in group A the LDV did not participate in the model explaining the variability of the FN BMD values. In group B, the least dense vertebra was the only variable participating in the respective model (adjusted-R(2) = 37.7%). It is concluded that in a significant proportion of relatively young postmenopausal women, a wide variance of BMD values exists between individual vertebral BMD values without radiographic background. L1 was the most frequent LDV and L3 the most rare. In such cases, the evaluation of the least dense vertebra seems to offer an alternative estimation of vertebral bone mass, instead of mean L1-L4.

Absorptiometry, Photon↗

PubMed2002

Clamped-filament elongation model for actin-based motors.

Although actin-based motility drives cell crawling and intracellular locomotion of organelles and certain pathogens, the underlying mechanism of force generation remains a mystery. Recent experiments demonstrated that Listeria exhibit episodes of 5.4-nm stepwise motion corresponding to the periodicity of the actin filament subunits, and extremely small positional fluctuations during the intermittent pauses [S. C. Kuo and J. L. McGrath. 2000. Nature. 407:1026-1029]. These findings suggest that motile bacteria remain firmly bound to actin filament ends as they elongate, a behavior that appears to rule out previous models for actin-based motility. We propose and analyze a new mechanochemical model (called the "Lock, Load & Fire" mechanism) for force generation by means of affinity-modulated, clamped-filament elongation. During the locking step, the filament's terminal ATP-containing subunit binds tightly to a clamp situated on the surface of a motile object; in the loading step, actin.ATP monomer(s) bind to the filament end, an event that triggers the firing step, wherein ATP hydrolysis on the clamped subunit attenuates the filament's affinity for the clamp. This last step initiates translocation of the new ATP-containing terminus to the clamp, whereupon another cycle begins anew. This model explains how surface-tethered filaments can grow while exerting flexural or tensile force on the motile surface. Moreover, stochastic simulations of the model reproduce the signature motions of Listeria. This elongation motor, which we term actoclampin, exploits actin's intrinsic ATPase activity to provide a simple, high-fidelity enzymatic reaction cycle for force production that does not require elongating filaments to dissociate from the motile surface. This mechanism may operate whenever actin polymerization is called upon to generate the forces that drive cell crawling or intracellular organelle motility.

Actins↗

PubMed2003

Drug craving and addiction: integrating psychological and neuropsychopharmacological approaches.

In the present review, an integrated approach to craving and addiction is discussed, which is based on recent insights from psychology and neuropsychopharmacology. An integrated model explains craving and relapse in humans by the psychological mechanism of "attentional bias" and provides neuropsychopharmacological mechanisms for this bias. According to this model, cognitive processes mediate between drug stimulus and the subject's response to this stimulus and subsequent behavioral response (e.g., drug use, relapse). According to the model, a conditioned drug stimulus produces an increase in dopamine levels in the corticostriatal circuit, in particular the anterior cingulate gyrus, amygdala, and nucleus accumbens, which in turn serves to draw the subject's attention towards a perceived drug stimulus. This process results in motor preparation and a hyperattentive state towards drug-related stimuli that, ultimately, promotes further craving and relapse. Evidence for this attentional bias hypothesis is reviewed from both the psychopharmacological and the neuroanatomical viewpoints. The attentional bias hypothesis raises several suggestions for clinical approaches and further research.

Attention↗

PubMed2001

A Bragg glass phase in the vortex lattice of a type II superconductor.

Although crystals are usually quite stable, they are sensitive to a disordered environment: even an infinitesimal amount of impurities can lead to the destruction of crystalline order. The resulting state of matter has been a long-standing puzzle. Until recently it was believed to be an amorphous state in which the crystal would break into 'crystallites'. But a different theory predicts the existence of a novel phase of matter: the so-called Bragg glass, which is a glass and yet nearly as ordered as a perfect crystal. The 'lattice' of vortices that contain magnetic flux in type II superconductors provide a good system to investigate these ideas. Here we show that neutron-diffraction data of the vortex lattice provides unambiguous evidence for a weak, power-law decay of the crystalline order characteristic of a Bragg glass. The theory also predicts accurately the electrical transport properties of superconductors; it naturally explains the observed phase transitions and the dramatic jumps in the critical current associated with the melting of the Bragg glass. Moreover, the model explains experiments as diverse as X-ray scattering in disordered liquid crystals and the conductivity of electronic crystals.

Journal Article↗

PubMed1998

[Transitory global amnesia--psychogenic origin of organic disease? Psychopathologic basis and pathogenetic considerations].

Transient global amnesia (TGA) is an acute amnestic syndrome without neurological symptoms and remitting spontaneously. Though cerebral ischemia, epilepsy, and migraine have been implicated in some cases, non of these factors could be proven responsible for most, and etiology remains unclear. Of special interest is the induction of TGA by psychological and emotional stress in about 14-29% of all cases, which is illustrated by the clinical example of a 72-year-old women who suffered an attack of TGA after discovering a burglary in her home. Psychopathological and pathogenetic aspects are discussed in the context of recent neurobiological memory research. This suggests that TGA involves transient dysfunction of a specific memory subsystem associated with hippocampal structures. Neural network modelling explains the syndrome of TGA on a pathogenetic basis allowing for heterogeneous etiology and even for psychogenic release. Thus TGA serves as a model for pathogenetic explanation in the neuro-psychiatric borderland.

Acute Disease↗

PubMed2000

Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C.

The population pharmacokinetics of ribavirin were assessed in patients with chronic hepatitis C virus (HCV) infection treated with interferon alpha-2b and ribavirin in four clinical efficacy studies. The authors collected 3450 ribavirin serum concentrations from 1105 patients at different treatment weeks for inclusion in the analysis. Population factors included gender, age, body weight, serum creatinine, creatinine clearance, and previous interferon treatment history. Ribavirin apparent clearance (CL/F) was calculated from individual patients' daily doses divided by concentration values, and the influence of these factors was assessed by multiple regression. Body weight, gender, age, and serum creatinine affected CL/F. Population mean CL/F estimates were 17.9 L/h (female) and 21.5 L/h (male) assuming an age of 40 years and body weight of 70 kg. Ribavirin apparent clearance increased as a function of body weight and decreased at ages greater than 40 years. Serum creatinine had little influence on CL/F, which may reflect the relatively normal renal function of these patients. Total CL/F variability was approximately 28%. The four covariates in the model explained 27% of this variability, and were thus of limited clinical significance because of the substantial residual variability not accounted for by the model. In assessing the relationship between pharmacokinetics and pharmacodynamics, the week 4 hemoglobin nadir value was negatively associated with week 4 ribavirin concentrations. The percentage of reduction from baseline was positively associated with ribavirin concentrations, although these data were highly variable. Loss of HCV-RNA at 24 weeks after completion of treatment was considered a response to interferon and ribavirin treatment in a logistic regression analysis of clinical and pharmacokinetic variables and treatment response in the interferon-naive patients. Hepatitis C virus genotype, pretreatment HCV-RNA titer, duration of treatment period, week 4 ribavirin concentration, and patient age affected the likelihood of response. Higher ribavirin concentrations at treatment week 4 were associated with a higher response rate. Variables that have predictive value for treatment outcome in patients treated with interferon and ribavirin are similar to those previously reported for interferon monotherapy.

Adult↗

PubMed2025

Mechanisms of enhanced or impaired DNA target selectivity driven by protein dimerization.

Successful DNA transcription demands coordination between proteins that bind DNA while simultaneously binding to one another to form dimers or higher-order complexes. For proteins with numerous DNA targets throughout the genome, measurements that report on their dwell time or occupancy thus represent a convolution over a population interacting with specific DNA, nonspecific DNA, or protein partners on DNA. Dimerization is known to add contacts that can help a single protein to stably bind DNA. However, we show here that dimerization can also impair measured dwell times and occupancy on target sequences because the population redistributes across DNA. We combine mass-action kinetic models of pairwise reversible reactions between proteins and DNA with theory and spatial stochastic simulations to isolate the role of dimerization on observed DNA dwell times, occupancy, and spatial distribution of proteins on DNA. Three key themes emerge: (i) Protein-protein interactions, in addition to protein-DNA interactions, can localize a protein to DNA, and relative binding rates can thus widely tune dwell times. (ii) Dimensional reduction achieved through nonspecific binding and subsequent 1D diffusion controls the order-of-magnitude of enhancements despite nucleosome barriers. (iii) Dimerization enhances selectivity for locally clustered targets and often impairs binding to widely-spaced targets by sequestration. Compared with ChIP-seq data, our model explains how the distribution of the essential GAF protein throughout the genome is highly selective for clustered targets due to protein interactions. This model framework predicts when even weak dimerization can redistribute and stabilize proteins on DNA as a necessary part of transcription.

DNA binding↗

PubMed2004

A steady-state modeling approach to validate an in vivo mechanism of the GAL regulatory network in Saccharomyces cerevisiae.

Cellular regulation is a result of complex interactions arising from DNA-protein and protein-protein binding, autoregulation, and compartmentalization and shuttling of regulatory proteins. Experiments in molecular biology have identified these mechanisms recruited by a regulatory network. Mathematical models may be used to complement the knowledge-base provided by in vitro experimental methods. Interactions identified by in vitro experiments can lead to the hypothesis of multiple candidate models explaining the in vivo mechanism. The equilibrium dissociation constants for the various interactions and the total component concentration constitute constraints on the candidate models. In this work, we identify the most plausible in vivo network by comparing the output response to the experimental data. We demonstrate the methodology using the GAL system of Saccharomyces cerevisiae for which the steady-state analysis reveals that Gal3p neither dimerizes nor shuttles between the cytoplasm and the nucleus.

Binding Sites↗

PubMed2002

A model of prefrontal cortex dopaminergic modulation during the delayed alternation task.

Working memory performance is modulated by the level of dopamine (DA) D1 receptors stimulation in the prefrontal cortex (PFC). This modulation is exerted at different time scales. Injection of D1 agonists/antagonists exerts a long-lasting influence (several minutes or hours) on PFC pyramidal neurons. In contrast, during performance of a cognitive task, the duration of the postsynaptic effect of phasic DA release is short lasting. The functional relationships of these two time scales of DA modulation remain poorly understood. Here we propose a model that combines these two time scales of DA modulation on a prefrontal neural network. The model links the cellular and behavioral levels during performance of the delayed alternation task. The network, which represents the activity of deep-layer pyramidal neurons with intrinsic neuronal properties, exhibits two stable states of activity that can be switched on and off by excitatory inputs from long-distance cortical areas arriving in superficial layers. These stable states allow PFC neurons to maintain representations during the delay period. The role of an increase of DA receptors stimulation is to restrict inputs arriving on the prefrontal network. The model explains how the level of working memory performance follows an inverted U-shape with an increased stimulation of DA D1 receptors. The model predicts that (1) D1 receptor agonists increase perseverations, (2) D1 antagonists increase distractability, and (3) the duration of the postsynaptic effect of phasic DA release in the PFC is adjusted to the delay period of the task. These results show how the precise duration of the postsynaptic effect of phasic DA release influences behavioral performance during a simple cognitive task.

Dopamine↗

PubMed1994

Response element selectivity for heterodimerization of vitamin D receptors with retinoic acid and retinoid X receptors.

The transcription of vitamin D (VD) responsive genes is regulated by three different nuclear signalling pathways mediated by homodimers of VD receptors (VDRs), heterodimers of VDRs and retinoid X receptors (RXRs) and heterodimers of VDRs with retinoic acid receptors (RARs), Here, the in vitro DNA-binding affinity of all three receptor complexes was shown to be enhanced by the presence of VD. However, the specificity of the three pathways was dictated by the differential affinities of the receptor complexes for VD response elements. Potential response elements were distinguished by the sequence, the separation and the relative orientation of the hexameric core binding motifs. It was found that both VDR-RAR and VDR-RXR heterodimers act functionally on all three response element configurations: direct repeats, palindromes and inverted palindromes. With direct repeats, neither heterodimer type showed a preference for any of the three principal core motifs, (A/G)GGTGA, (A/G)GGTCA and (A/G)GTTCA. However, while they did exhibit preferences for core motifs in palindromes, the spacing requirements were identical for both complexes. Inverted palindromes, however, formed the most specific response elements. A simple model explains a steric link between the optimal spacing of direct repeats and that of inverted palindromes. Taken together, the experimental data and the model provide further criteria for the screening of VD responsive genes.

Animals↗

PubMed2002

Brain-potential evidence for the time course of access to biographical facts and names of familiar persons.

On seeing familiar persons, biographical (semantic) information is typically retrieved faster and more accurately than name information. Serial stage models explain this pattern by suggesting that access to the name follows the retrieval of semantic information. In contrast, interactive activation and competition (IAC) models hold that both processes start together but name retrieval is slower because of structural peculiarities. With a 2-choice go/no-go procedure based on a semantic and a name-related classification, the authors tested differential predictions of the 2 alternative models for reaction times (RTs) and lateralized readiness potentials (LRP). Both LRP (Experiment 1) and RT (Experiment 2) results are in line with IAC models of face identification and naming.

Biographies as Topic↗

PubMed1984

Up- and down-regulation of insulin receptors. Kinetic models.

A theoretical model for insulin receptor synthesis and degradation in differentiating 3T3-L1 adipocytes is described. This three-step irreversible ordered sequence model explains the up- and down-regulation of receptors in terms of the level of insulin concentration. Kinetic expressions were derived for the model. Numerical solutions for these equations, based on data reported by Reed and Lane (Reed, B.C., and Lane, M. D. (1980) Proc. Natl. Acad. Sci. U.S.A. 77, 285-289) were used for computer-generated curves illustrating insulin-dependent receptor synthesis and degradation. Results show that this model provides the best fit to the reported data and lend support to the suggestion that the free recycled receptor may differ from the newly synthesized receptor. A possible role for the recycled receptor in signal modulation is suggested.

Adipose Tissue↗

PubMedDate not supplied

Eye position signals in the vestibular nuclei: consequences for models of integrator function.

Recordings from neurons in the vestibular nuclei indicate that the cells that carry eye position signals encode the position of a single eye (either ipsilateral or contralateral) during both conjugate and vergence eye movements. The fact that the vestibular nuclei are aware of the positions of each eye is not surprising as the otolith-based linear vestibulo-ocular reflex is known to change its behaviour as a function of uniocular eye position. This result suggests that the signal coming from the oculomotor velocity-to-position integrator specifies the position of each eye during vergence movements and thus must receive a vergence velocity input along with its conjugate velocity inputs. As there is no vergence system in laterally eyed animals, we have proposed two possible models of integrator arrangement that could have developed from conjugate directional (rather than uniocular) integrators in lower animals without frontally mounted eyes. Both of these models explain the existence of near-response cells and produce the required bidirectional gaze paretic nystagmus following unilateral lesions of one integrator. The models also make specific and different predictions concerning the effects of unilateral integrator lesions on the behaviour of the vergence system and thus make suggestions for further experiments.

Animals↗

PubMed1993

Joint impairment and self-reported disability in elderly persons.

Recent findings indicating that arthritis is a major contributor to disability in elderly persons are based on self-reported diagnostic information. We conducted physical examinations of the joints at baseline on 541 older persons. We then tested a multivariate model of total/generic disability which included respondent group, demographic and chronic disease variables (joint impairment and comorbid conditions), arthritis pain, and psychological status. Hierarchical multiple regression found that the model explained 55 percent (adjusted R2 = .55) of the variance in baseline disability with joint impairment accounting for 15 percent (change in R2 = .15) of the variance. When joint impairment was removed from the model, arthritis pain worked well as a surrogate. Together, these findings strongly support the importance of musculoskeletal disease in explaining disability in the elderly population.

Activities of Daily Living↗