Statistical mechanics for metabolic networks during steady-state growth

Which properties of metabolic networks can be derived solely from stoichiometric information about the network's constituent reactions? Predictive results have been obtained by Flux Balance Analysis (FBA), by postulating that cells set metabolic fluxes within the allowed stoichiometry so as to maximize their growth. Here, we generalize this framework to single cell level using maximum entropy models from statistical physics. We define and compute, for the core metabolism of Escherichia coli, a joint distribution over all fluxes that yields the experimentally observed growth rate. This solution, containing FBA as a limiting case, provides a better match to the measured fluxes in the wild type and several mutants. We find that E. coli metabolism is close to, but not at, the optimality assumed by FBA. Moreover, our model makes a wide range of predictions: (i) on flux variability, its regulation, and flux correlations across individual cells; (ii) on the relative importance of stoichiometric constraints vs. growth rate optimization; (iii) on quantitative scaling relations for singe-cell growth rate distributions. We validate these scaling predictions using data from individual bacterial cells grown in a microfluidic device at different sub-inhibitory antibiotic concentrations. Under mild dynamical assumptions, fluctuation-response relations further predict the autocorrelation timescale in growth data and growth rate adaptation times following an environmental perturbation.Comment: 12 pages, 4 figure

The medical treatment of Cushing's disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery

BACKGROUND: The role of dopamine agonists in the treatment of Cushing's disease (CD) has been previously debated. AIM: The aim of this study was to evaluate the effectiveness of short-term (3 months) and long-term (12-24 months) treatment with cabergoline in patients with CD. Patients and Methods: 20 patients with CD unsuccessfully treated by surgery entered the study. Cabergoline was administered at an initial dose of 1 mg/wk, with a monthly increase of 1 mg, until urinary cortisol levels normalized or the maximal dose of 7 mg/wk was achieved. The responsiveness to treatment was evaluated according to changes in urinary cortisol excretion. A decrease greater than 25% was considered as a partial response, whereas complete normalization was considered as a full response at short-term evaluation; persistence of normal cortisol excretion was the only criterion to evaluate the response at long-term evaluation. RESULTS: After short-term treatment, 15 (75%) patients were responsive to cabergoline treatment. Among these, normalization of cortisol excretion was maintained in 10, whereas treatment escape was observed in five patients after 6-18 months. Among the 10 long-term responsive patients, eight were followed for 24 months, whereas the remaining two were followed for 12-18 months, due to cabergoline withdrawal for intolerance. A sustained control of cortisol secretion for 24 month cabergoline treatment at the maximal dose ranging from 1-7 mg/wk (median: 3.5) without significant side effects, was obtained in eight of 20 (40%) patients. CONCLUSIONS: The results of this study demonstrated that cabergoline treatment is effective in controlling cortisol secretion for at least 1-2 yr in more than one third of a limited population of patients with CD. If this evidence is confirmed by additional studies, this agent may be considered as a useful treatment option in patients with CD who are unsuccessfully treated by neurosurgery

Learning to coordinate in a complex and non-stationary world

We study analytically and by computer simulations a complex system of adaptive agents with finite memory. Borrowing the framework of the Minority Game and using the replica formalism we show the existence of an equilibrium phase transition as a function of the ratio between the memory $\lambda$ and the learning rates $\Gamma$ of the agents. We show that, starting from a random configuration, a dynamic phase transition also exists, which prevents the system from reaching any Nash equilibria. Furthermore, in a non-stationary environment, we show by numerical simulations that agents with infinite memory play worst than others with less memory and that the dynamic transition naturally arises independently from the initial conditions.Comment: 4 pages, 3 figure

Hereditary Deficiency of gp91(phox) Is Associated With Enhanced Arterial Dilatation Results of a Multicenter Study

Background-NADPH oxidase is believed to modulate arterial tone, but its role in humans is still unclear. The objective of this study was to evaluate whether NADPH oxidase is involved in flow-mediated arterial dilation (FMD). Methods and Results-Twenty-five patients with hereditary deficiency of gp91(phox), the catalytic core of NADPH oxidase, (X-CGD), 25 healthy subjects, and 25 obese patients matched for sex and age were recruited. FMD, platelet gp91(phox), serum levels of nitrite and nitrate as markers of nitric oxide generation, oxidized low-density lipoprotein, and urinary excretion of isoprostanes as markers of oxidative stress were determined. Platelet gp91(phox) expression was downregulated in X-CGD patients (1.0+/-0.8 mean fluorescence; P<0.001) and upregulated in obese patients (4.1+/-2.2 mean fluorescence; P=0.01) compared with healthy subjects (2.9+/-1.7 mean fluorescence). Urinary excretion of isoprostanes was reduced in X-CGD patients (41.7+/-33.3 pg/mg creatinine; P = 0.04) and increased in obese patients (154.4+/-91 pg/mg creatinine; P<0.001) compared with healthy subjects (69.5+/-52.4 pg/mg creatinine). Obese patients had higher serum oxidized low-density lipoprotein than healthy subjects (35.3+/-6.7 versus 24.8+/-9.8 U/L; P<0.001) and X-CGD patients (28.5+/-7.2 U/L; P<0.001). X-CGD patients had significantly higher FMD (14.7+/-5.9%) compared with healthy subjects (7.9+/-2.5%; P<0.001); obese patients had lower FMD (5.3+/-3.0%; P+/-0.028) compared with healthy subjects. Serum nitrite and nitrate levels were significantly higher in patients with X-CGD (36.0+/-10.8+/-mol/L; P<0.016) and lower in obese patients (9.3+/-11.0 mu mol/L; P<0.001) compared with healthy subjects (27.1+/-19.1 mu mol/L). Serum nitrite and nitrate levels significantly correlated with FMD (R-s = 0.403, P<0.001) and platelet gp91(phox) (R-s = -0.515, P<0.001). FMD inversely correlated with platelet gp91(phox) (R-s = -0.502, P<0.001) and isoprostanes (R-s = -0.513, P<0.001). Conclusion-This study provides the first evidence that, in humans, gp91(phox) is implicated in the modulation of arterial ton

Blocking spinal CCR2 with AZ889 reversed hyperalgesia in a model of neuropathic pain

<p>Abstract</p> <p>Background</p> <p>The CCR2/CCL2 system has been identified as a regulator in the pathogenesis of neuropathy-induced pain. However, CCR2 target validation in analgesia and the mechanism underlying antinociception produced by CCR2 antagonists remains poorly understood. In this study, <it>in vitro </it>and <it>in vivo </it>pharmacological approaches using a novel CCR2 antagonist, AZ889, strengthened the hypothesis of a CCR2 contribution to neuropathic pain and provided confidence over the possibilities to treat neuropathic pain with CCR2 antagonists.</p> <p>Results</p> <p>We provided evidence that dorsal root ganglia (DRG) cells harvested from CCI animals responded to stimulation by CCL2 with a concentration-dependent calcium rise involving PLC-dependent internal stores. This response was associated with an increase in evoked neuronal action potentials suggesting these cells were sensitive to CCR2 signalling. Importantly, treatment with AZ889 abolished CCL2-evoked excitation confirming that this activity is CCR2-mediated. Neuronal and non-neuronal cells in the spinal cord were also excited by CCL2 applications indicating an important role of spinal CCR2 in neuropathic pain. We next showed that in vivo spinal intrathecal injection of AZ889 produced dose-dependent analgesia in CCI rats. Additionally, application of AZ889 to the exposed spinal cord inhibited evoked neuronal activity and confirmed that CCR2-mediated analgesia involved predominantly the spinal cord. Furthermore, AZ889 abolished NMDA-dependent wind-up of spinal withdrawal reflex pathway in neuropathic animals giving insight into the spinal mechanism underlying the analgesic properties of AZ889.</p> <p>Conclusions</p> <p>Overall, this study strengthens the important role of CCR2 in neuropathic pain and highlights feasibility that interfering on this mechanism at the spinal level with a selective antagonist can provide new analgesia opportunities.</p

Evidence for interhemispheric imbalance in stroke patients as revealed by combining transcranial magnetic stimulation and electroencephalography

Interhemispheric interactions in stroke patients are frequently characterized by abnormalities, in terms of balance and inhibition. Previous results showed an impressive variability, mostly given to the instability of motor-evoked potentials when evoked from the affected hemisphere. We aim to find reliable interhemispheric measures in stroke patients with a not-evocable motor-evoked potential from the affected hemisphere, by combining transcranial magnetic stimulation (TMS) and electroencephalography. Ninteen stroke patients (seven females; 61.26 ± 9.8 years) were studied for 6 months after a first-ever stroke in the middle cerebral artery territory. Patients underwent four evaluations: clinical, cortical, corticospinal, and structural. To test the reliability of our measures, the evaluations were repeated after 3 weeks. To test the sensitivity, 14 age-matched healthy controls were compared to stroke patients. In stroke patients, stimulation of the affected hemisphere did not result in any inhibition onto the unaffected. The stimulation of the unaffected hemisphere revealed a preservation of the inhibition mechanism onto the affected. This resulted in a remarkable interhemispheric imbalance, whereas this mechanism was steadily symmetric in healthy controls. This result was stable when cortical evaluation was repeated after 3 weeks. Importantly, patients with a better recovery of the affected hand strength were the ones with a more stable interhemispheric balance. Finally, we found an association between microstructural integrity of callosal fibers, suppression of interhemispheric TMS-evoked activity and interhemispheric connectivity. We provide direct and sensitive cortical measures of interhemispheric imbalance in stroke patients. These measures offer a reliable means of distinguishing healthy and pathological interhemispheric dynamics

Emotion based attentional priority for storage in visual short-term memory

A plethora of research demonstrates that the processing of emotional faces is prioritised over non-emotive stimuli when cognitive resources are limited (this is known as ‘emotional superiority’). However, there is debate as to whether competition for processing resources results in emotional superiority per se, or more specifically, threat superiority. Therefore, to investigate prioritisation of emotional stimuli for storage in visual short-term memory (VSTM), we devised an original VSTM report procedure using schematic (angry, happy, neutral) faces in which processing competition was manipulated. In Experiment 1, display exposure time was manipulated to create competition between stimuli. Participants (n = 20) had to recall a probed stimulus from a set size of four under high (150 ms array exposure duration) and low (400 ms array exposure duration) perceptual processing competition. For the high competition condition (i.e. 150 ms exposure), results revealed an emotional superiority effect per se. In Experiment 2 (n = 20), we increased competition by manipulating set size (three versus five stimuli), whilst maintaining a constrained array exposure duration of 150 ms. Here, for the five-stimulus set size (i.e. maximal competition) only threat superiority emerged. These findings demonstrate attentional prioritisation for storage in VSTM for emotional faces. We argue that task demands modulated the availability of processing resources and consequently the relative magnitude of the emotional/threat superiority effect, with only threatening stimuli prioritised for storage in VSTM under more demanding processing conditions. Our results are discussed in light of models and theories of visual selection, and not only combine the two strands of research (i.e. visual selection and emotion), but highlight a critical factor in the processing of emotional stimuli is availability of processing resources, which is further constrained by task demands

Meta-Analysis and Systematic Review of Neural Stem Cells therapy for experimental ischemia stroke in preclinical studies

To evaluate the preclinical studies using NSCs transplantation therapy for experimental ischemic stroke, and determine the effect size of NSCs therapy and the correlations between different clinical measures. We firstly searched literatures to identify studies of NSCs therapy in animal cerebral ischemia models, and then calculated the quality score of studies, assessed the effect size of NSCs therapy relative to behavioral and histologic endpoints by meta-analysis. A total of 37 studies and 54 independent treated interventions were used for systematic review and meta-analysis. The median quality score was 5 of 10. 36 studies (53 intervention arms) reported functional outcome, 22 studies (34 intervention arms) reported structural outcome. After adjusted by subgroup and sensitivity analysis, the mean effect sizes were improved by 1.35 for mNSS, 1.84 for rotarod test, 0.61 for cylinder test, and 0.84 for infarct volume. Furthermore, effect size had a certain interaction with clinical variables, for example early NSCs therapy etc. In this preclinical studies, we demonstrated that transplanted NSCs significantly improved outcomes (both functional and structural outcome) in ischemic stroke. It is suggested that future preclinical animal model studies of stroke should improve study quality validity and reduce potentially confounded publication bias

Intergenerational and intrafamilial phenotypic variability in 22q11.2 deletion syndrome subjects

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is a common microdeletion syndrome, which occurs in approximately 1:4000 births. Familial autosomal dominant recurrence of the syndrome is detected in about 8-28% of the cases. Aim of this study is to evaluate the intergenerational and intrafamilial phenotypic variability in a cohort of familial cases carrying a 22q11.2 deletion. METHODS: Thirty-two 22q11.2DS subjects among 26 families were enrolled. RESULTS: Second generation subjects showed a significantly higher number of features than their transmitting parents (212 vs 129, P = 0.0015). Congenital heart defect, calcium-phosphorus metabolism abnormalities, developmental and speech delay were more represented in the second generation (P < 0.05). Ocular disorders were more frequent in the parent group. No significant difference was observed for the other clinical variables. Intrafamilial phenotypic heterogeneity was identified in the pedigrees. In 23/32 families, a higher number of features were found in individuals from the second generation and a more severe phenotype was observed in almost all of them, indicating the worsening of the phenotype over generations. Both genetic and epigenetic mechanisms may be involved in the phenotypic variability. CONCLUSIONS: Second generation subjects showed a more complex phenotype in comparison to those from the first generation. Both ascertainment bias related to patient selection or to the low rate of reproductive fitness of adults with a more severe phenotype, and several not well defined molecular mechanism, could explain intergenerational and intrafamilial phenotypic variability in this syndrome