Literatura académica sobre el tema "Correction de la diffusion cellulaire"

Background Susac Syndrome (SuS) is an autoimmune endotheliopathy impacting the brain, retina and cochlea that can clinically mimic multiple sclerosis (MS). Objective To evaluate non-lesional white matter demyelination changes in SuS compared to MS and healthy controls (HC) using quantitative MRI. Methods 3T MRI including myelin water imaging and diffusion basis spectrum imaging were acquired for 7 SuS, 10 MS and 10 HC participants. Non-lesional white matter was analyzed in the corpus callosum (CC) and normal appearing white matter (NAWM). Groups were compared using ANCOVA with Tukey correction. Results SuS CC myelin water fraction (mean 0.092) was lower than MS(0.11, p = 0.01) and HC(0.11, p = 0.04). Another myelin marker, radial diffusivity, was increased in SuS CC(0.27μm2/ms) compared to HC(0.21μm2/ms, p = 0.008) and MS(0.23μm2/ms, p = 0.05). Fractional anisotropy was lower in SuS CC(0.82) than HC(0.86, p = 0.04). Fiber fraction (reflecting axons) did not differ from HC or MS. In NAWM, radial diffusivity and apparent diffusion coefficient were significantly increased in SuS compared to HC(p < 0.001 for both measures) and MS(p = 0.003, p < 0.001 respectively). Conclusions Our results provided evidence of myelin damage in SuS, particularly in the CC, and more extensive microstructural injury in NAWM, supporting the hypothesis that there are widespread microstructural changes in SuS syndrome including diffuse demyelination.

Despite its increasing use in physiological animal investigations, there has been no systematic study of the whole body kinetics of 2-deoxy-D-glucose (2DG) or its modification by insulin. A previously proposed model that included processes representing transport across cell walls and intracellular phosphorylation of 2DG was investigated. The model predictions were compared with the plasma disappearance of 2DG observed in the rat following intravenous bolus injection. Experiments were performed during euglycemia at varying levels of hyperinsulinemia. The model was adequate to describe empirically the experimental data after a correction was made for urine loss. However, the variation in model parameters with plasma insulin concentration was not consistent with the expected action of insulin on cellular efflux. A possible explanation could be a shift in the rate-limiting step from glucose transport to another prephosphorylation process under conditions of high tissue uptake. This suggests that either intracellular or extracellular diffusion may constitute a significant barrier to 2DG (and glucose) uptake under some conditions.

The aim of this study is to examine the antioxidant and antiapoptotic activity of liposomal α-tocopherol (LAT) in anesthetized rats exposed to severe hypoxia. It was shown that intratracheal application of LAT normalized lung phospholipid composition and inhibited lipid peroxidation in lung tissues, which in turn decreased lung edema and damage and improved breathing pattern, oxygen diffusion, and lung gas exchange. LAT also limited the overexpression of genes encoding hypoxia inducible factor-1α and both studied forms of phospholipase A2, and it increased the power of cellular antioxidant and antiapoptotic defense by overexpressing genes encoding Mn- and Cu-Zn-cofactored superoxide dismutases, Bcl-2, and heat shock 70 proteins. The overexpression of studied caspases and their activity were downregulated, which significantly (1.6–2 times) limited apoptosis in lung cells. Finally, all these positive changes decreased mortality during hypoxia from ∼60% in untreated animals to ∼30% in the group of rats treated with LAT. The data obtained indicate that LAT may be useful for the correction of hypoxic lung injury.

The cell-to-medium distribution ratios at steady state of L-arginine (RArg) and of the lipid-soluble cation tetraphenylphosphonium (RTPP) were studied as a function of the membrane potential (Em) in adult human fibroblasts. The relationship between RArg and Em was qualitatively similar to that of RTPP and Em. Quantitatively, RArg and RTPP differed in that 1) RTPP was much greater than RArg when Em was near zero, indicating a significant binding component in the uptake of TPP+ but not of L-arginine, and 2) after a correction for binding when Em is near zero, RTPP was still greater than RArg so that RT/F . ln RTPP exceeded RT/F . ln RArg by 10-25 mV. The pattern of the redistribution of accumulated TPP+ and arginine after an alteration of Em was identical. In null-point experiments, the external [K+] for which there were no changes in cellular TPP+ or L-arginine in the presence of high valinomycin (the null points) were very similar for the two probes. Em calculated from the null-point measurements (-70(-)-80 mV) was also very similar to RT/F . ln RArg and thus smaller than RT/F.ln RTPP. It was concluded that 1) there was an additional TPP+ binding as cellular [TPP] rose in response to more negative membrane potentials, 2) the transport system for L-arginine in these cells (system y+) operates as a facilitated diffusion system driven by the membrane potential, and 3) in some circumstances, L-arginine could be employed as a probe of Em.

Cell encapsulation has been shown to hold promise for effective, long-term treatment of type 1 diabetes (T1D). However, challenges remain for its clinical applications. For example, there is an unmet need for an encapsulation system that is capable of delivering sufficient cell mass while still allowing convenient retrieval or replacement. Here, we report a simple cell encapsulation design that is readily scalable and conveniently retrievable. The key to this design was to engineer a highly wettable, Ca2+-releasing nanoporous polymer thread that promoted uniform in situ cross-linking and strong adhesion of a thin layer of alginate hydrogel around the thread. The device provided immunoprotection of rat islets in immunocompetent C57BL/6 mice in a short-term (1-mo) study, similar to neat alginate fibers. However, the mechanical property of the device, critical for handling and retrieval, was much more robust than the neat alginate fibers due to the reinforcement of the central thread. It also had facile mass transfer due to the short diffusion distance. We demonstrated the therapeutic potential of the device through the correction of chemically induced diabetes in C57BL/6 mice using rat islets for 3 mo as well as in immunodeficient SCID-Beige mice using human islets for 4 mo. We further showed, as a proof of concept, the scalability and retrievability in dogs. After 1 mo of implantation in dogs, the device could be rapidly retrieved through a minimally invasive laparoscopic procedure. This encapsulation device may contribute to a cellular therapy for T1D because of its retrievability and scale-up potential.

In this paper, we introduce and study one-dimensional models for the behavior of pedestrians in a narrow street or corridor. We begin at the microscopic level by formulating a stochastic cellular automata model with explicit rules for pedestrians moving in two opposite directions. Coarse-grained mesoscopic and macroscopic analogs are derived leading to the coupled system of PDEs for the density of the pedestrian traffic. The obtained first-order system of conservation laws is only conditionally hyperbolic. We also derive higher-order nonlinear diffusive corrections resulting in a parabolic macroscopic PDE model. Numerical experiments comparing and contrasting the behavior of the microscopic stochastic model and the resulting coarse-grained PDEs for various parameter settings and initial conditions are performed. These numerical experiments demonstrate that the nonlinear diffusion is essential for reproducing the behavior of the stochastic system in the nonhyperbolic regime.

<p style="text-align: justify;">La cinétique de diffusion des composés phénoliques de la baie de raisin varie selon l'origine de ces pigments. Ceux des pellicules diffusent plus rapidement que ceux des pépins. En plus, au sein même des pellicules, les tanins diffusent plus lentement que les anthocyanes. Il apparaÎt, contrairement aux tanins, que la diffusion des anthocyanes en milieu aqueux ne varie pas au cours de la maturation. Ceci est dû à la nature des pigments et à leur localisation. Ainsi, la maturation du raisin est accompagnée par la diminution des teneurs en pectines pariétales des pellicules et par la fragilisation des parois cellulaires déterminée par des traitements aux ultra-sons. Un indice de maturité cellulaire et des indices de diffusion des pigments sont alors déterminés. Ces indices montrent que la diffusion des tanins est influencée par la fragilité des parois cellulaires alors que celle des anthocyanes est indépendante de cette fragilité. Les phénomènes de diffusion des composés phénoliques lors de la vinification sont alors mis en évidence.</p>

Résumé Dans cet article, nous problématisons l’appropriation de controverses sociotechniques par le biais de l’utilisation d’outils théoriques développés dans le domaine des science & technology studies. Nous présentons d’abord les notions de représentation délégative et de traduction ainsi que trois modèles d’interactions des citoyens avec les scientifiques. Puis nous interprétons le point de vue d’étudiants de niveau collégial sur les capacités et rôles des citoyens concernés par la controverse autour de la téléphonie cellulaire de même que sur l’objet de la controverse, la constitution des collectifs de recherche et la diffusion des savoirs.

Cette thèse présente une nouvelle stratégie de modélisation pour le suivi en ligne des bioréacteurs, utilisant la spectroscopie Raman et Machine Learning. L'objectif principal de cette étude est de développer des modèles simplifiés utilisant des spectres Raman provenant d'étalons. Elle se compose de trois parties.La première partie de cette thèse consiste à optimiser les paramètres d'acquisition Raman et à élaborer un modèle de régression PLS en utilisant des étalons purs. Ensuite, une validation préliminaire est entreprise en employant des étalons mixtes afin de simuler les variations de composition moléculaire dans le milieu, au cours du procédé, la fermentation alcoolique. La deuxième partie propose une expression non linéaire pour interpréter l'atténuation Raman due à la présence de micro-organismes dans un bioréacteur réel, permettant ainsi la correction des spectres diffusés par les cellules. Pour évaluer la performance du modèle, des bioréacteurs batch et fed-batch ont été réalisés, afin de confirmer la fiabilité et la robustesse prédictive de la stratégie de correction et du modèle de régression élaborés. Enfin, la troisième partie met en lumière les avantages de la méthodologie de modélisation proposée, comparativement à l'approche traditionnelle utilisant les spectres des bioréacteurs pour l'entraînement du modèle de régression.Dans l'ensemble, cette approche innovante a démontré une excellente performance de prédiction sur tous les ensembles de données de validation et de test, présentant un potentiel significatif pour l'ingénierie des bioprocédés. Elle permet un suivi plus précis et plus efficace de plusieurs composés en temps réel, et améliore le contrôle et l'optimisation des processus. La stratégie proposée devrait avoir une application étendue dans l'industrie de la bioproduction
This thesis presents a novel and reproducible modeling strategy for online monitoring of bioreactors using Raman spectroscopy and Machine Learning. The main aim of this study is to develop simplified models using the Raman spectra of standards in solution. It consists of three key parts.The first part involves optimizing Raman acquisition parameters and developing a PLS regression model using pure standards. Subsequently, a preliminary validation was carried out using mixed standards to mimic changes in the composition of different molecules in the medium during the alcoholic fermentation process. The second part defined a nonlinear expression to interpret the Raman attenuation induced by the presence of microorganisms in a real bioreactor, allowing the correction of cell--scattered spectra. For model evaluation, numerous batches and one fed--batch bioreactor were launched to validate the working performance and predictive robustness of the obtained correction strategy and regression model. The third part highlights the advantages of our proposed modeling methodology over the traditional way that uses the spectra from bioreactors to train the regression model.Overall, the innovative approach demonstrated an excellent prediction performance on all validation and testing datasets, presenting significant potential for bioprocess engineering. It enables more accurate and efficient monitoring of multiple compounds in real time, as well as enhances process control and optimization. The proposed strategy is expected to have an extended application in the bioproduction industry

En imagerie scintigraphique, la detection de rayonnement diffuse est l'une des principales causes de la deterioration de la qualite des images, en terme de resolution spatiale, de contraste et d'interpretation quantitative. La technique classique d'acquisition dans une fenetre en energie, bien qu'elle amoindrisse les effets du rayonnement diffuse, reste peu satisfaisante. Parmi les nombreuses methodes de correction qui ont ete proposees, aucune solution reellement adaptee ne s'est imposee. La methode de correction de la diffusion que nous developpons repose sur l'analyse factorielle des sequences d'images medicales (afsim). L'afsim permet de resoudre un modele de superposition lineaire pose sur un ensemble de donnees (ici les spectres locaux des photons detectes durant l'acquisition), et conduit a l'estimation de fonctions fondamentales sous-jacentes (ici un spectre de photons non diffuses et des spectres de photons diffuses) et des distributions spatiales associees (l'image des photons non diffuses et celles des photons diffuses). La methode classique d'afsim, ainsi que les variantes auxquelles elle a donne lieu, ne permettent pas d'obtenir la decomposition spectrale recherchee. Ses differentes etapes sont donc modifiees pour introduire des connaissances a priori relatives aux proprietes statistiques des donnees traitees et aux proprietes physiques des solutions recherchees. Nous montrons que les performances de la methode ainsi remaniee et sa fiabilite sont accrues. Elle s'avere alors un outil adapte a la correction de la diffusion des differents examens scintigraphiques: planaires et tomographiques, mono et multi-isotopiques, statiques et dynamiques. La correction de la diffusion est evaluee au moyen de simulations numeriques, de simulations de monte carlo, d'acquisitions sur fantomes et d'acquisitions cliniques. La correction s'adapte a chaque ensemble de donnees, donc a chaque patient et aux caracteristiques du detecteur, et est applicable quels que soient les radioelements utilises. Elle permet d'ameliorer la quantification en imagerie scintigraphique

Diffusion magnetic resonance imaging (MRI) is useful for studying the diseased, dysfunctional, and healthy human brain. Unfortunately, this technique is susceptible to geometric distortions that decrease the accuracy and value of the data. A distortion correction algorithm must be used to remedy these issues during post-processing. The purpose of this thesis is to develop, implement, and test a distortion correction method for diffusion weighted MRI. A distortion correction algorithm was designed and implemented and then tested on simulated and real human brain datasets. The algorithm was found to work well for simulated datasets with b-values up to and including b=2000 s/(mm*mm). Furthermore, the cause of distortion correction failures were investigated. Failures are believed to be due to a combination of reduced signal to noise ratio (SNR) and increased contrast differences in datasets with higher b-values.
L'imagerie par résonance magnétique (IRM) de diffusion est utile dans l'étude du cerveau humain, tant en santé que dysfonctionnel ou atteint de maladie. Malheureusement, cette technique est susceptible à des distortions géometriques qui diminuent la précision et la valeur des données. Un algorithme de correction de ces distortions doit être utilisé pendant le traitement des données. Le but de ce mémoire est de développer, d'implementer et de tester une méthode de correction des distortions pour l'IRM de diffusion. Un algorithme de correction des distortions fut developé et implémenté, puis évalué sur des ensembles de données cérébrales humaines simulées et réelles. L'algorithme fonctionne bien pour des données simulées avec des valeurs b jusqu'à b=2000 s/(mm*mm). La cause des échecs de la correction de distortion fut également étudiée. Les échecs sont attribués à une combinaison de la réduction du rapport signal sur bruit (SNR, pour signal-to-noise ratio) et de l'augmentation des différences de contraste, dans les ensembles de données avec des valeurs-b plus élevées.

La thérapie génique sans transfert de gène utilisant les endonucléases de restriction spécifiques est une des approches thérapeutiques qui visent à la mise au point d’un traitement curatif de la dystrophie musculaire de Duchenne (DMD). Afin de corriger le gène de la dystrophine avec les nucléases à doigt de zinc (ZFNs) en ciblant l’exon 50, nous avons produit les protéines ZFNs dans les bactéries et les avons purifiées. Les résultats obtenus après les essais in vitro montrent que les ZFNs produites reconnaissent d’une manière spécifique la séquence cible située au niveau de l’exon 50 du gène DYS et peuvent y générer d’une manière précise les coupures double-brin. Ils montrent également que les protéines ZFNs produites peuvent être transfectées, avec ou sans agent de transfection, dans les myoblastes des patients dystrophiques Duchenne en culture.
Gene therapy without gene transfer using specific restriction endonucleases is a therapeutic approaches aimed at the development of a cure for Duchenne muscular dystrophy (DMD). To correct the dystrophin gene with zinc finger nucleases (ZFNs) targeting exon 50of DYS gene, we produced ZFNs proteins in bacteria and purified them. The results obtained after in vitro assays show that ZFNs produced specifically recognize a target sequence located in exon 50 of the gene DYS and can be generated in a precise manner the double strand breaks. They also show that ZFNs produced proteins can be transduced with or without agent transduction, in cultured myoblasts of patients’ Duchenne dystrophy.

Les mutations non-sens représentent environ 10% des mutations trouvées dans les maladiesgénétiques héréditaires. Les ARNm portant une mutation non-sens sont dégradés par un mécanismeappelé nonsense-mediated mRNA decay (NMD) pour empêcher la synthèse de protéines tronquéesqui pourraient être toxiques ou non-fonctionnelles pour la cellule. Plusieurs stratégies ont étédéveloppées pour sauver une mutation non-sens. Dans notre laboratoire, nous étudions deux d'entreelles qui sont (i) l'inhibition du NMD et (ii) l'activation de la translecture du PTC qui est un mécanismeconduisant à l'incorporation d'un acide aminé à la position du PTC. Pour trouver de nouveauxmoyens thérapeutiques pour les maladies génétiques héréditaires, notre laboratoire a testédifférentes molécules par criblage, pour identifier celles qui ont la capacité d'inhiber le NMD. Chaquemolécule sélectionnée par le crible est étudiée afin de mesurer son efficacité d'inhibition du NMD etd'activation de la translecture. Nous avons ainsi montré que i'amlexanox non seulement inhibe NMDmais active également la translecture du PTC. Cependant, l'efficacité de I'amlexanox reste modeste.Nous avons donc recherché d'autres familles de molécules qui sont capables de sauver une mutationnon-sens et qui ont une efficacité de correction des mutations non sens meilleure ou démontrentune plus grande spécificité. Dans mon étude, j'ai trouvé deux familles de protéines particulières quesont les inducteurs d'apoptose et les inhibiteurs du cytosquelette. J'ai trouvé que les inducteursd'apoptose peuvent inhiber le NMD en activant les caspases qui clivent les facteurs du NMD (UPF1 etUPF2). J'ai aussi montré que les inhibiteurs du cytosquelette peuvent inhiber le NMD et que certainsd'entre eux peuvent activer la translecture de PTC en induisant les facteurs du NMD (UPF1 et / ouUPF3X) à se concentrer dans les P-bodies et/ou dans d'autres foyers cytoplasmiques. Les rendementsde ces molécules sur l'inhibition du NMD sont similaires ou meilleure que I'amlexanox. Les inducteursd'apoptose et les inhibiteurs du cytosquelette nous démontrent qu'il est possible de trouver desmolécules très différentes capables de corriger des mutations non sens avec une bonne efficacité
Nonsense mutations represent approximately 10% of mutations found in the inherited geneticdiseases. mRNAs harboring a nonsense mutation are rapidly degraded by a quality-controlmechanism called nonsense-mediated mRNA decay (NMD) to prevent the synthesis of toxic or nonfunctionaltruncated proteins. Some stratégies have been developed to correct nonsense mutations.In our lab, we study 2 of them which are (i) the NMD inhibition and (ii) the PTC-readthroughactivation which is a mechanism leading to the incorporation of an amino-acid at the PTC position. Todesign new therapeutic tools for the inherited genetic diseases, our lab tested molecules byscreening to find ones with the capacity of NMD inhibition. For each molecules selected in thescreen, we measure the efficiency of NMD inhibition and PTC-readthrough activation of thesemolecules in cell lines harboring a nonsense mutation. We have shown that amlexanox not onlyinhibits NMD but also activâtes PTC readthrough. But the efficacy of amlexanox is still low. Wewanted to find other families of molecules capable of rescuing the expression of nonsense mutationcontainingmRNA with a higher efficacy or with some specificity. In my study, I found two spécialfamilies, one is the family of apoptosis inducers and the other is the family of cytoskeleton inhibitors.I found that apoptosis inducers can inhibit NMD by activating caspase pathway and cleave NMDfactors (UPF1 and UPF2). I also found that cytoskeleton inhibitors can inhibit NMD and some of themcan activate PTC-readthrough by inducing NMD factors (UPF1 or/and UPF3X) to concentrate in Pbodiesor in other cytoplasmic foci. The efficiencies of these molecules on NMD inhibition are similaror higher than amlexanox. Apoptosis inducers and cytoskeleton inhibitors demonstrated thatmolecules which can inhibit NMD or/and activate PTC-readthrough can be found and candemonstrate a higher correction of nonsense mutation efficiency than the existing molecules(ataluren or amlexanox for example)

Dans cette thèse, nous avons concentré notre étude sur les mécanismes qui génèrent la polarité cellulaire, en particulier dans le cas de la migration cellulaire. Malgré les derniers développements concernant l’observation de l’activité des RhoGTPases, les principes qui dictent la capacité des cellules à coordonner plusieurs modules de signalisation en parallèle ne sont toujours pas compris. L’optogénétique est un outil d’intérêt pour disséquer ces réseaux de signalisation à partir de la création d’une perturbation dont les caractéristiques spatiotemporelles sont contrôlées. Tout d’abord, à partir de la caractérisation des différents processus biophysiques en jeu, nous avons établi les relations quantitatives entre l’illumination et les gradients moléculaires que l’on induit. Nous avons déterminé qu’il est possible de créer des gradients subcellulaires avec une résolution spatiale de l’ordre de 5 μm et temporelle d’environ 3 minutes Ensuite, nous avons utilisé cette approche optogénétique pour contrôler l’activité de Cdc42, Rac1 et RhoA. Nous avons caractérisé les effets subcellulaires de l’activation de ces RhoGTPases en utilisant l’activité de membrane, les changements de forme cellulaire et leurs déplacements comme rapporteurs de la polarisation et de la migration. Nous avons ainsi montré qu’une activation locale de RhoGTPase permet la réorganisation interne des cellules jusqu’à générer un phénotype de migration.Enfin, nous avons caractérisé les effets d’une activation locale de RhoA sur différents acteurs moléculaires comme les points focaux d’adhésion, l’actine et les moteurs moléculaires myosines. Nous avons mesuré alors la dynamique de l’intégration des points focaux dans le cytosquelette et analysé la réponse du réseau d’acto-myosine au cours d’évènements de rétraction.Notre approche optogénétique couple le contrôle d’une perturbation à la mesure de la réponse cellulaire simultanément de manière directe et reproductible. Elle apporte une méthode pour contrôler la polarité cellulaire et une manière de disséquer des réseaux de signalisation à l’échelle subcellulaire
In this thesis we focus on the mechanisms that establish cell polarization, particularly during cell migration. Despite latest developments that enable visualization of RhoGTPases activity, the underlying principles dictating the cell’s ability to coordinates multiple signaling modules is still unclear. Optogenetic methods have been recognized as promising tools to dissect these intracellular signaling networks by allowing perturbations to be spatially and temporally controlled. We established the quantitative relationship between illumination patterns and the corresponding gradients of induced signaling activity through the characterization of the biophysical properties of CRY2/CIBN. We determined that it is possible to create subcellular gradients of recruited proteins of different shapes of choice up to spatial resolutions of 5μm and temporal ones of ca. 3 minutes.We applied the aforementioned optogenetic approach as a means to perturb the activity of cdc42, Rac1 and RhoA. We characterized the effects of subcellular activation of those RhoGTPases using membrane activity, cell shape changes and cell displacement as reporters of cell polarization and migration. We show that localized activation of RhoGTPases can trigger cellular organization and drive the cell into a migrating state.We also characterized the effects of local activation of RhoA on different cellular effectors as focal adhesion complexes, actin filaments and myosin molecular motors. We measured the dynamics of the newly formed focal adhesion complexes and the acto-myosin complex during retraction events.Altogether, our optogenetic methodology enables simultaneous measurement of the imposed perturbation and the cell response in a straightforward and reproducible way. It provides a quantitative way to control cell polarity and a step forward in the dissection of subcellular signaling networks

Nous presentons une nouvelle methode de correction du diffuse compton en scintigraphie. Cette methode utilise la technologie des reseaux neuro-mimetiques (rnm). Les spectres d'energie de chaque pixel et de son entourage sont utilises comme valeurs d'entrees du reseau. On recueille en sortie la fraction non-diffusee estimee du pixel. La phase d'apprentissage est effectuee a partir d'images provenant d'une simulation de monte-carlo. Le reseau ainsi entraine est ensuite applique lors de la phase de restitution a une simulation scintigraphique differente mais aussi sur fantomes reels. Plusieurs architectures sont experimentees. Dans la plus simple, les donnees d'entree sont reduites au seul pixel examine. Les autres modeles utilisent en plus des informations tirees de son voisinage. La methode a ete evaluee a la fois sur acquisition reelle et simulee et ses resultats compares a ceux obtenus par d'autres methodes courantes montrent que l'utilisation des rnm est une voie prometteuse pour la correction de diffuse compton en scintigraphie

1. Macroeconomic Summary In December, headline inflation (13.1%) and the average of the core inflation measures (10.3%) continued to trend upward, posting higher rates than those estimated by the Central Bank's technical staff and surpassing the market average. Inflation expectations for all terms exceeded the 3.0% target. In that month, every major group in the Consumer Price Index (CPI) registered higher-than-estimated increases, and the diffusion indicators continued to show generalized price hikes. Accumulated exchange rate pressures on prices, indexation to high inflation rates, and several food supply shocks would explain, in part, the acceleration in inflation. All of this is in a context of significant surplus demand, a tight labor market, and inflation expectations at different terms that exceed the 3.0% target. Compared to the October edition of the Monetary Policy Report, the forecast path for headline and core inflation (excluding food and regulated items: EFR) increased (Graphs 1.1 and 1.2), reflecting heightened accumulated exchange rate pressures, price indexation to a higher inflation rate (CPI and the producer price index: PPI), and the rise in labor costs attributed to a larger-than-estimated adjustment in the minimum wage. Nevertheless, headline inflation is expected to begin to ease by early 2023, although from a higher level than had been estimated in October. This would be supported initially by the slowdown forecast for the food CPI due to a high base of comparison, the end anticipated for the shocks that have affected the prices of these products, and the estimated improvement in external and domestic supply in this sector. In turn, the deterioration in real household income because of high inflation and the end of the effects of pent-up demand, plus tighter external and domestic financial conditions would contribute to diluting surplus demand in 2023 and reducing inflation. By the end of 2023, both headline and core (EFR) inflation would reach 8.7% and would be 3.5% and 3.8%, respectively, by December 2024. These forecasts are subject to a great deal of uncertainty, especially concerning the future behavior of international financial conditions, the evolution of the exchange rate, the pace of adjustment in domestic demand, the extent of indexation of nominal contracts, and the decisions taken regarding the domestic price of fuel and electricity. In the third quarter, economic activity surprised again on the upside and the growth projection for 2022 rose to 8.0% (previously 7.9%). However, it declined to 0.2% for 2023 (previously 0.5%). With this, surplus demand continues to be significant and is still expected to weaken during the current year. Annual economic growth in the third quarter (7.1 % SCA)1 was higher than estimated in October (6.4 % SCA), given stronger domestic demand specifically because of higher-than-expected investment. Private consumption fell from the high level witnessed a quarter earlier and net exports registered a more negative contribution than anticipated. For the fourth quarter, economic activity indicators suggest that gross domestic product (GDP) would have remained high and at a level similar to that observed in the third quarter, with an annual variation of 4.1%. Domestic demand would have slowed in annual terms, although at levels that would have remained above those for output, mainly because of considerable private consumption. Investment would have declined slightly to a value like the average observed in 2019. The real trade deficit would have decreased due to a drop in imports that was more pronounced than the estimated decline in exports. On the forecast horizon, consumption is expected to decline from current elevated levels, partly because of tighter domestic financial conditions and a deterioration in real income due to high inflation. Investment would also weaken and return to levels below those seen before the pandemic. In real terms, the trade deficit would narrow due to a lower momentum projection for domestic demand and higher cumulative real depreciation. In sum, economic growth for all of 2022, 2023, and 2024 would stand at 8.0%, 0.2% and 1.0%, respectively (Graph 1.3). Surplus demand remains high (as measured by the output gap) and is expected to decline in 2023 and could turn negative in 2024 (Graph 1.4). Although the macroeconomic forecast includes a marked slowdown in the economy, an even greater adjustment in domestic absorption cannot be ruled out due to the cumulative effects of tighter external and domestic financial conditions, among other reasons. These estimates continue to be subject to a high degree of uncertainty, which is associated with factors such as global political tensions, changes in international interest rates and their effects on external demand, global risk aversion, the effects of the approved tax reform, the possible impact of reforms announced for this year (pension, health, and labor reforms, among others), and future measures regarding hydrocarbon production. In 2022, the current account deficit would have been high (6.3 % of GDP), but it would be corrected significantly in 2023 (to 3.9 % of GDP) given the expected slowdown in domestic demand. Despite favorable terms of trade, the high external imbalance that would occur during 2022 would be largely due to domestic demand growth, cost pressures associated with high freight rates, higher external debt service payments, and good performance in terms of the profits of foreign companies.2 By 2023, the adjustment in domestic demand would be reflected in a smaller current account deficit especially due to fewer imports, a global moderation in prices and cost pressures, and a reduction in profits remitted abroad by companies with foreign direct investment (FDI) focused on the local market. Despite this anticipated correction in the external imbalance, its level as a percentage of GDP would remain high in the context of tight financial conditions. In the world's main economies, inflation forecasts and expectations point to a reduction by 2023, but at levels that still exceed their central banks' targets. The path anticipated for the Federal Reserve (Fed) interest rate increased and the forecast for global growth continues to be moderate. In the fourth quarter of 2022, logistics costs and international prices for some foods, oil and energy declined from elevated levels, bringing downward pressure to bear on global inflation. Meanwhile, the higher cost of financing, the loss of real income due to high levels of global inflation, and the persistence of the war in Ukraine, among other factors, have contributed to the reduction in global economic growth forecasts. In the United States, inflation turned out to be lower than estimated and the members of the Federal Open Market Committee (FOMC) reduced the growth forecast for 2023. Nevertheless, the actual level of inflation in that country, its forecasts, and expectations exceed the target. Also, the labor market remains tight, and fiscal policy is still expansionary. In this environment, the Fed raised the expected path for policy interest rates and, with this, the market average estimates higher levels for 2023 than those forecast in October. In the region's emerging economies, country risk premia declined during the quarter and the currencies of those countries appreciated against the US dollar. Considering all the above, for the current year, the Central Bank's technical staff increased the path estimated for the Fed's interest rate, reduced the forecast for growth in the country's external demand, lowered the expected path of oil prices, and kept the country’s risk premium assumption high, but at somewhat lower levels than those anticipated in the previous Monetary Policy Report. Moreover, accumulated inflationary pressures originating from the behavior of the exchange rate would continue to be important. External financial conditions facing the economy have improved recently and could be associated with a more favorable international context for the Colombian economy. So far this year, there has been a reduction in long-term bond interest rates in the markets of developed countries and an increase in the prices of risky assets, such as stocks. This would be associated with a faster-than-expected reduction in inflation in the United States and Europe, which would allow for a less restrictive course for monetary policy in those regions. In this context, the risks of a global recession have been reduced and the global appetite for risk has increased. Consequently, the risk premium continues to decline, the Colombian peso has appreciated significantly, and TES interest rates have decreased. Should this trend consolidate, exchange rate inflationary pressures could be less than what was incorporated into the macroeconomic forecast. Uncertainty about external forecasts and their impact on the country remains high, given the unpredictable course of the war in Ukraine, geopolitical tensions, local uncertainty, and the extensive financing needs of the Colombian government and the economy. High inflation with forecasts and expectations above 3.0%, coupled with surplus demand and a tight labor market are compatible with a contractionary stance on monetary policy that is conducive to the macroeconomic adjustment needed to mitigate the risk of de-anchoring inflation expectations and to ensure that inflation converges to the target. Compared to the forecasts in the October edition of the Monetary Policy Report, domestic demand has been more dynamic, with a higher observed level of output exceeding the productive capacity of the economy. In this context of surplus demand, headline and core inflation continued to trend upward and posted surprising increases. Observed and expected international interest rates increased, the country’s risk premia lessened (but remains at high levels), and accumulated exchange rate pressures are still significant. The technical staff's inflation forecast for 2023 increased and inflation expectations remain well above 3.0%. All in all, the risk of inflation expectations becoming unanchored persists, which would accentuate the generalized indexation process and push inflation even further away from the target. This macroeconomic context requires consolidating a contractionary monetary policy stance that aims to meet the inflation target within the forecast horizon and bring the economy's output to levels closer to its potential. 1.2 Monetary Policy Decision At its meetings in December 2022 and January 2023, Banco de la República’s Board of Directors (BDBR) agreed to continue the process of normalizing monetary policy. In December, the BDBR decided by a majority vote to increase the monetary policy interest rate by 100 basis points (bps) and in its January meeting by 75 bps, bringing it to 12.75% (Graph 1.5). 1/ Seasonally and calendar adjusted. 2/ In the current account aggregate, the pressures for a higher external deficit come from those companies with FDI that are focused on the domestic market. In contrast, profits in the mining and energy sectors are more than offset by the external revenue they generate through exports. Box 1 - Electricity Rates: Recent Developments and Indexation. Author: Édgar Caicedo García, Pablo Montealegre Moreno and Álex Fernando Pérez Libreros Box 2 - Indicators of Household Indebtedness. Author: Camilo Gómez y Juan Sebastián Mariño