Identifying quantitative operation principles in metabolic pathways: a systematic method for searching feasible enzyme activity patterns leading to cellular adaptive responses

Background: Optimization methods allow designing changes in a system so that specific goals are attained. These techniques are fundamental for metabolic engineering. However, they are not directly applicable for investigating the evolution of metabolic adaptation to environmental changes. Although biological systems have evolved by natural selection and result in well-adapted systems, we can hardly expect that actual metabolic processes are at the theoretical optimum that could result from an optimization analysis. More likely, natural systems are to be found in a feasible region compatible with global physiological requirements. Results: We first present a new method for globally optimizing nonlinear models of metabolic pathways that are based on the Generalized Mass Action (GMA) representation. The optimization task is posed as a nonconvex nonlinear programming (NLP) problem that is solved by an outer- approximation algorithm. This method relies on solving iteratively reduced NLP slave subproblems and mixed-integer linear programming (MILP) master problems that provide valid upper and lower bounds, respectively, on the global solution to the original NLP. The capabilities of this method are illustrated through its application to the anaerobic fermentation pathway in Saccharomyces cerevisiae. We next introduce a method to identify the feasibility parametric regions that allow a system to meet a set of physiological constraints that can be represented in mathematical terms through algebraic equations. This technique is based on applying the outer-approximation based algorithm iteratively over a reduced search space in order to identify regions that contain feasible solutions to the problem and discard others in which no feasible solution exists. As an example, we characterize the feasible enzyme activity changes that are compatible with an appropriate adaptive response of yeast Saccharomyces cerevisiae to heat shock Conclusion: Our results show the utility of the suggested approach for investigating the evolution of adaptive responses to environmental changes. The proposed method can be used in other important applications such as the evaluation of parameter changes that are compatible with health and disease states.

Aging preferentially affects molecular pathways implicated in development and disease of myelinating glial cells

The central and peripheral nervous systems are involved in multiple agedependent neurological deficits that are often attributed to alterations in function of myelinating glial cells. However, the molecular events that underlie the age-related decline of glial cell function are unknown. We used Schwann cells as a model to study biological processes affected in glial cells by aging. We comprehensively profiled gene expression of the Schwann cell-rich mouse sciatic nerve throughout life, from day of birth until senescence (840 days of age). We combined the aging data with the microarray transcriptional data obtained using nerves isolated from Schwann cell-specific neuropathy-inducing mutants MPZCre/þ/Lpin1fE2-3/fE2-3, MPZCre/þ/ScapfE1/fE1 and Pmp22-null mice. A majority of age related transcripts were also affected in the analyzed mouse models of neuropathy (54.4%) and in development (59.5%) indicating a high level of overlapping in implicated molecular pathways. We observed that compared to peripheral nerve development, dynamically changing expression profiles in aging have opposite (anticorrelated) orientation while they copy the orientation of transcriptional changes observed in analyzed neuropathy models. Subsequent clustering and biological annotation of dynamically changing transcripts revealed that the processes most significantly deregulated in aging include inflammatory/ immune response and lipid biosynthesis/metabolism. Importantly, the changes in these pathways were also observed in myelinated oligodendrocyte- rich optic nerves of aged mice, albeit with lower magnitude. This observation suggests that similar biological processes are affected in aging glial cells in central and peripheral nervous systems, however with different dynamics. Our data, which provide the first comprehensive comparison of molecular changes in glial cells in three distinct biological conditions comprising development, aging and disease, provide not only a new inside into the molecular alterations underlying neural system aging but also identify target pathways for potential therapeutical approaches to prevent or delay complications associated with age-related and inherited forms of neuropathies.

Once and for all - How people change strategy to ignore irrelevant information in visual tasks

Ignoring irrelevant visual information aids efficient interaction with task environments. We studied how people, after practice, start to ignore the irrelevant aspects of stimuli. For this we focused on how information reduction transfers to rarely practised and novel stimuli. In Experiment 1, we compared competing mathematical models on how people cease to fixate on irrelevant parts of stimuli. Information reduction occurred at the same rate for frequent, infrequent, and novel stimuli. Once acquired with some stimuli, it was applied to all. In Experiment 2, simplification of task processing also occurred in a once-for-all manner when spatial regularities were ruled out so that people could not rely on learning which screen position is irrelevant. Apparently, changes in eye movements were an effect of a once-for-all strategy change rather than a cause of it. Overall, the results suggest that participants incidentally acquired knowledge about regularities in the task material and then decided to voluntarily apply it for efficient task processing. Such decisions should be incorporated into accounts of information reduction and other theories of strategy change in skill acquisition.

Single-trial multisensory memories affect later auditory and visual object discrimination.

Multisensory memory traces established via single-trial exposures can impact subsequent visual object recognition. This impact appears to depend on the meaningfulness of the initial multisensory pairing, implying that multisensory exposures establish distinct object representations that are accessible during later unisensory processing. Multisensory contexts may be particularly effective in influencing auditory discrimination, given the purportedly inferior recognition memory in this sensory modality. The possibility of this generalization and the equivalence of effects when memory discrimination was being performed in the visual vs. auditory modality were at the focus of this study. First, we demonstrate that visual object discrimination is affected by the context of prior multisensory encounters, replicating and extending previous findings by controlling for the probability of multisensory contexts during initial as well as repeated object presentations. Second, we provide the first evidence that single-trial multisensory memories impact subsequent auditory object discrimination. Auditory object discrimination was enhanced when initial presentations entailed semantically congruent multisensory pairs and was impaired after semantically incongruent multisensory encounters, compared to sounds that had been encountered only in a unisensory manner. Third, the impact of single-trial multisensory memories upon unisensory object discrimination was greater when the task was performed in the auditory vs. visual modality. Fourth, there was no evidence for correlation between effects of past multisensory experiences on visual and auditory processing, suggestive of largely independent object processing mechanisms between modalities. We discuss these findings in terms of the conceptual short term memory (CSTM) model and predictive coding. Our results suggest differential recruitment and modulation of conceptual memory networks according to the sensory task at hand.

Circadian clock orchestration of signaling pathways influences mouse metabolism

Circadian clocks, present in organisms leaving in a rhythmic environment, constitute the mechanisms allowing anticipation and adaptation of behavior and physiology in response to these environmental variations. As a consequence, most aspects of metabolism and behavior are under the control of this circadian clock. At a molecular level, in all the studied species, the rhythmic expression of the genes involved are generated by interconnected transcriptional and translational feedback loops. In mammals, the heterodimer composed of BMAL1 and its partners CLOCK or NPAS2 constitutes a transcriptional activator regulating transcription of Per and Cry genes. These genes encode for repressors of the activity of BMAL1:CLOCK or BMAL1: NPAS2 heterodimers, thus closing a negative feedback loop that generates rhythms of approximately 24 hours. The aim of my doctoral work consisted in the investigation of the role of circadian clock in the regulation of different aspects of mouse metabolism through the rhythmic activation of signaling pathways. First, we showed that one way how the circadian clock exerts its function as an oscillator is through the regulation of mRNA translation. Indeed, we present evidence showing that circadian clock influences the temporal translation of a subset of mRNAs involved in ribosome biogenesis by controlling the transcription of translation initiation factors as well as the clock-dependent rhythmic activation of signaling pathways involved in their regulation. Moreover, the circadian oscillator regulates the transcription of ribosomal protein mRNAs and ribosomal RNAs. Thus the circadian clock exerts a major role in coordinating transcription and translation steps underlying ribosome biogenesis. In the second part, we showed the involvement of the circadian clock in lipid metabolism. Indeed, the three PAR bZip transcription factors DBP, TEF and HLF, are regulated by the molecular clock and play key roles in the control of lipid metabolism. Here we present evidence concerning the circadian expression and activity of PPARα via the circadian transcription of genes involved in the release of fatty acids, natural ligands of PPARα. It leads to the rhythmic activation of PPARα itself which could then play its role in the transcription of genes encoding proteins involved in lipid, cholesterol and glucose metabolism. In addition, we considered the possible role of lipid transporters, here SCP2, in the modulation of circadian activation of signaling pathways such as TORC1, PPARα and SREBP, linked to metabolism, and its feedback on the circadian clock. In the last part of this work, we studied the effects of these circadian clock-orchestrated pathways in physiology, as clock disruptions have been shown to be linked to metabolic disorders. We performed in vivo experiments on genetically and high-fat induced obese mice devoid of functional circadian clock. The results obtained showed that clock disruption leads to impaired triglycerides and glucose homeostasis in addition to insulin secretion and sensitivity. -- Les rythmes circadiens, présents chez tout organisme vivant dans un environnement rythmique, constituent l'ensemble de mécanismes permettant des réponses comportementales et physiologiques anticipées et adaptées aux variations environnementales. De ce fait, la plupart des aspects liés au métabolisme et au comportement de ces organismes apparaissent être sous le contrôle de l'horloge circadienne contrôlant ces rythmes. Au niveau moléculaire, dans toutes les espèces étudiées, l'expression rythmique de gènes impliqués sont générés par l'interconnexion de boucles de contrôle transcriptionnelles et traductionnelles. Chez les mammifères, l'hétérodimère composé de BMAL1 et de ses partenaires CLOCK ou NPAS2 constitue un activateur transcriptionnel régulant la transcription des gènes Per et Cry. Ces gènes codent pour des répresseurs de l'activité des hétérodimères BMAL1:CLOCK ou BMAL1:NPAS2. Cela a pour effet de fermer la boucle négative, générant ainsi des rythmes d'environ 24 heures. Le but de mon travail de thèse a consisté en l'investigation du rôle de l'horloge circadienne dans la régulation de certains aspects du métabolisme chez la souris via la régulation de l'activation rythmique des voies de signalisation. Nous avons tout d'abord montré que l'horloge circadienne exerce sa fonction d'oscillateur notamment au niveau de la régulation de la traduction des ARNm. En effet, nous présentons des preuves montrant que l'horloge circadienne influence la traduction temporelle d'un groupe d'ARNm impliqués dans la biogénèse des ribosomes en contrôlant la transcription de facteurs d'initiation de la traduction ainsi que l'activation rythmique des voies de signalisation qui sont impliquées dans leur régulation. De plus, l'oscillateur circadien régule la transcription d'ARNm codant pour les protéines ribosomales et d'ARN ribosomaux. De cette façon, l'horloge circadienne exerce un rôle majeur dans la coordination des étapes de transcription et traduction permettant la biogénèse des ribosomes. Dans la deuxième partie, nous montrons les implications de l'horloge circadienne dans le métabolisme des lipides. En effet, DBP, TEF et HLF, trois facteurs de transcription de la famille des PAR bZip qui sont régulés par l'horloge circadienne, jouent un rôle clé dans le contrôle du métabolisme des lipides par l'horloge circadienne. Nous apportons ici des preuves concernant l'expression et l'activité rythmiques de PPARα via la transcription circadienne de gènes impliqués dans le relargage d'acides gras, ligands naturels de PPARα, conduisant à l'activation circadienne de PPARα lui-même, pouvant ainsi jouer son rôle de facteur de transcription de gènes codant pour des protéines impliquées dans le métabolisme des lipides, du cholestérol et du glucose. De plus, nous nous sommes penchés sur le rôle possible de transporteurs de lipides, ici SCP2, dans la modulation de l'activation circadienne de voies de signalisation, telles que TORC1, PPARα et SREBP, qui sont liées au métabolisme, ainsi que son impact sur l'horloge elle-même. Dans la dernière partie de ce travail, nous avons étudié les effets de l'activation de ces voies de signalisation régulées par l'horloge circadienne dans le contexte physiologique puisqu'il a été montré que la perturbation de l'horloge pouvait être associée à des désordres métaboliques. Pour ce faire, nous avons fait des expériences in vivo sur des souris déficientes pour l'horloge moléculaire pour lesquelles l'obésité est induite génétiquement ou induite par la nourriture riche en lipides. Les résultats que nous obtenons montrent des dérèglements au niveau de l'homéostasie des triglycérides et du glucose ainsi que sur l'expression et la réponse à l'insuline.

Prospective pathways between heroin use and nonmedical use of prescription opioids: Trajectories among young Swiss men

BACKGROUND. So far few studies have focused on the last steps of drug-use trajectories. Heroin has been described as a final stage, but the non-medical use of prescription opioids (NMUPOs) is often associated with heroin use. There is, however, no consensus yet about which one precedes the other. AIMS. The objective of this study was to test which of these two substances was likely to be induced by the other using a prospective design. MATERIAL AND METHODS. We used data from the Swiss Longitudinal Cohort Study on Substance Use Risk Factors (C-SURF) to assess exposure to heroin and NMUPO at two times points (N = 5,041). Cross-lagged panel models provided evidence regarding prospective pathways between heroin and NMUPOs. Power analyses provided evidence about significance and clinical relevance. RESULTS. Results showed that heroin use predicted later NMUPO use (? = 1.217, p < 0.001) and that the reverse pathway was non-significant (? = 0.240, p = .233). Heroin use seems to be an important determinant, causing a 150% risk increase for NMUPO use at follow-up, whereas NMUPO use at baseline increases the risk of heroin use at follow-up by a mere non-significant 20%. CONCLUSIONS. Thus, heroin users were more likely to move to NMUPOs than non-heroin users, whereas NMUPO users were not likely to move to heroin use. The pathway of substance use seemed to include first heroin use, then NMUPO use.

Visual signs and symptoms in patients with the visual variant of Alzheimer disease.

BACKGROUND: Prominent visual symptoms can present in the visual variant of Alzheimer's disease (VVAD). Ophthalmologists have a significant role to play in the early diagnosis of VVAD. METHODS: We retrospectively reviewed the files of ten consecutive patients diagnosed with VVAD. All patients had a full neuro-ophthalmologic examination, a formal neurological and neuro-psychological testing, and cerebral MRI to confirm diagnosis. In addition, functional neuroimaging was obtained in seven patients. RESULTS: The common primary symptom at presentation with all patients was difficulty with near vision (reading difficulty n = 8, "visual blur" in near vision n = 2), and difficulty writing (n = 3). Following assessment, impaired reading and writing skills were evident in 9/10 and 8/10 patients respectively. Median distance visual acuity was 20/25 and at near the median visual acuity was J6. Partial homonymous visual field defect was detected in 80 % (8/10) of the patients. Color vision was impaired in all patients when tested with Ishihara pseudoisochromatic plates, but simple color naming was normal in 8/9 tested patients. Simultanagnosia was present in 8/10 patients. Vision dysfunction corresponded with cerebral MRI findings where parieto-occipital cortical atrophy was observed in all patients. PET scan (5 patients) or SPECT (2 patients) revealed parieto-occipital dysfunction (hypometabolism or hypoperfusion) in all 7 tested patients CONCLUSIONS: Visual difficulties are prominent in VVAD. Dyslexia, incomplete homonymous hemianopia, preserved color identification with abnormal color vision on Ishihara, and simultanagnosia were all symptoms observed frequently in this patient series. Ophthalmologists should be aware of the possibility of neurodegenerative disorders such as VVAD in patients with unexplained visual complaints, in particular reading difficulties.

Does chronic nicotine consumption influence visual backward masking in schizophrenia and schizotypy ?

Nicotine consumption is higher for people within the schizophrenia spectrum compared to controls. This observation supports the self-medication hypothesis, that nicotine relieves symptoms in, for example, schizophrenia patients. We tested whether performance in an endophenotype of schizophrenia (visual backward masking, VBM) is modulated by nicotine consumption in i) smoking and non-smoking schizophrenia patients, their first-degree relatives, and age-matched controls, ii) non-smoking and smoking university students, and iii) non-smoking, early and late onset nicotine smokers. Overall, our results confirmed that VBM deficits are an endophenotype of schizophrenia, i.e., deficits were highest in patients, followed by their relatives, students scoring high in Cognitive Disorganisation, and controls. Moreover, we found i) beneficial effects of chronic nicotine consumption on VBM performance, in particular with increasing age, and ii) little impact of clinical status. alone or in interactionwith nicotine consumption on VBMperformance. Given the younger age of undergraduate students (up to 30 years) versus controls and patients (up to 66 years),we propose that age-dependent VBMdeficits emergewhen schizotypy effects are targeted in populations of a larger age range, but that nicotine consumption might counteract these deficits (supporting the self-medication hypothesis).