Literatura académica sobre el tema "Voie des BMP"

Introduction Synthetic bone grafts are often used to achieve a well-consolidated fusion mass in spinal fusion procedures. These bone grafts function as scaffolds, and ideally support cell function and facilitate protein binding. Objective The aim was to characterize an electrospun, synthetic bone void filler (Reb) for its bone morphogenetic protein (BMP)-2 release properties and support of human mesenchymal stem cell (hMSC) function in vitro, and its efficacy in promoting BMP-2-/bone marrow aspirate-(BMA)-mediated posterolateral spinal fusion (PLF) in vivo. Methods BMP-2 release kinetics from Reb versus standard absorbable collagen sponge (ACS) was determined. hMSC adhesion and proliferation on Reb was tested using cell counting, fluorescence microscopy and MTS. Cell osteogenic differentiation was quantified via cellular alkaline phosphatase (ALP) activity. For in vivo analysis, 18 Lewis rats were treated during PLF surgery with the following groups: (I) Reb + BMA, (II) Reb + BMA + BMP-2 and (III) BMA. A safe, minimally effective dose of BMP-2 was used. Fusion consolidation was followed for 3 months using radiography and micro-CT. After sacrifice, fusion rate and biomechanical stiffness was determined using manual palpation, biomechanical tests and histology. Results In vitro, BMP-2 release kinetics were similar between Reb versus ACS. MSC proliferation and differentiation were increased in the presence of Reb. At 3 months post-surgery, fusion rates were 29% (group I), 100% (group II), and 0% (group III). Biomechanical stiffness was higher in group II versus I. Micro-CT showed an increased bone volume and connectivity density in group II. Trabecular thickness was increased in group I versus II. H&E staining showed newly formed bone in group II only. Conclusions Reb possesses a high protein binding affinity and promotes hMSC function. Combination with BMA and minimal dose BMP-2 allowed for 100% bone fusion in vivo. This data suggests that a minimally effective dose of BMP-2 can be used when combined with Reb.

The aim of this study was to compare the bone regeneration ability of particle and block bones, acting as bone scaffolds, with recombinant human bone morphogenetic protein (rhBMP)-2 and evaluate them as rhBMP-2 carriers. Demineralized bovine bone particles, blocks, and rhBMP-2 were grafted into the subperiosteal space of a rat calvarial bone, and the rats were randomly divided into four groups: particle, block, P (particle)+BMP, and B (block)+BMP groups. The bone volume of the B+BMP group was significantly higher than that of the other groups (p < 0.00), with no significant difference in bone mineral density. The average adipose tissue volume of the B+BMP group was higher than that of the P+BMP group, although the difference was not significant. Adipose tissue formation was observed in the rhBMP-2 application group. Histologically, the particle and B+BMP groups showed higher formation of a new bone. However, adipose tissue and void spaces were also formed, especially in the B+BMP group. Hence, despite the formation of a large central void space, rhBMP-2 could be effectively used with block bone scaffolds and showed excellent new bone formation. Further studies are required to evaluate the changes in adipose tissue.

Les bétons à hautes performances (BHP) sont des bétons qui présentent des résistances mécaniques élevées (> 60 MPa) et une micro texture très dense (faible porosité), qui empêche la pénétration des agents agressifs. Dans le contexte de ce travail une étude expérimentale a été faite à fin d’élaborer un béton BHP à base des matériaux locaux disponible dans la région de Béchar, dont le but de réduire le cout de BHP. Le deuxième objectif de ce travail est de voir l’influence du rapport E/C (0.3, 0.35, 0.4) sur le comportement rhéologique et physico-mécanique (la maniabilité, porosité, résistances à la compression, résistance à la flexion, l’absorption d’eau et la masse volumique) de BHP élaboré à base de pouzzolane naturelle de la région de Boukais (Bechar), et voir aussi l’effet de la pouzzolane naturelle qui a utilisé comme une substitution partielle dans le ciment portland (10% et 20%) sur le comportement physico-mécanique de BHP.

La myogenèse correspond à la formation de fibres musculaires multinucléés à partir de progéniteurs mononucléés. Les progéniteurs musculaires sont responsables de croissance musculaire au cours du développement (myogenèse embryonnaire et fœtale), de la période périnatale et lors du processus de régénération chez l’adulte. Les cellules progénitrices musculaires, exprimant le facteur de transcription Pax7, sont responsables de la croissance musculaire pendant la myogenèse fœtale. On ne connaît pas la nature et la source des facteurs régulant ces progéniteurs. Ce travail de thèse met en évidence qu’une sous-population de progéniteurs musculaires fœtaux localisée aux extrémités des muscles, proche des tendons répondent à la voie Bmp «Bone morphogenetic protein». Des expériences de gain et de perte de fonction de la voie de signalisation Bmp, chez l’embryon de poulet, en utilisant le système rétroviral RCAS, montre que la voie Bmp est impliquée dans la régulation de la myogenèse fœtale. La surexpression du ligand Bmp4 ou d’une forme constitutivement active du récepteur BmpRIA dans les membres de poulet conduit à une augmentation du nombre des progéniteurs fœtaux et des fibres musculaires fœtales. Inversement, le blocage de la voie Bmp en surexprimant l’antagoniste Noggin réduit le nombre de progéniteurs et de fibres musculaires. Cet effet de la voie Bmp est différent de celui observé au cours de la myogenèse embryonnaire et déduit des études in vitro. Cette étude souligne les différences entre les progéniteurs embryonnaires et progéniteurs fœtaux. Cette étude indique que la voie Bmp est impliquée dans la croissance longitudinale des muscles au cours du développement du membre.

Les lamines A et C sont deux composants majeurs de la lamina nucléaire, réseau de filaments intermédiaires situé sous la membrane nucléaire interne. Les mutations du gène LMNA, codant les lamines A/C, ont été associées à de nombreuses pathologies humaines, appelées laminopathies, et affectant un ou plusieurs tissus dont le muscle. Les mécanismes physiopathologiques sous-jacents ne sont encore que partiellement élucidés. Les lamines A/C jouant un rôle crucial dans l’architecture nucléaire et l’organisation de la chromatine, l’hypothèse d’une altération de l’expression de facteurs de transcription ou de gènes tissus-spécifiques a été formulée. De plus, au niveau musculaire, il a été décrit que les lamines A/C jouent un rôle majeur dans la mise en place d’une différenciation musculaire efficace.Afin d’identifier des altérations potentielles au sein des voies de signalisation régulant la différenciation musculaire, nous avons utilisés un modèle de myoblastes murins conditionnellement immortalisés et comparés le profil d’expression entre les myoblastes sauvages et inactivés pour le gène Lmna (Lmna-/-). Nous avons donc identifiés deux altérations majeures de la voie BMP (Bone Morphogenetic Pathway) : la diminution de l’expression du ligand Bmp4 et l’augmentation de celle de Smad6, un inhibiteur intracellulaire de la voie. Cette surexpression de Smad6 est responsable d’une séquestration cytoplasmique des Smads 1, 5 et 8 phosphorylées et d’une diminution de l’expression des gènes cibles, Id1 et Id2. Les myoblastes Lmna-/- montrent une différenciation myogénique prématurée, phénotype réversible par des expériences d’ARN interférent ciblant Smad6. Enfin, nous avons montré que ces défauts sont retrouvés dans des myoblastes humains porteurs hétérozygotes de la mutation LMNA R310X.Ces résultats apportent un nouveau mécanisme physiopathologique des laminopathies musculaires et identifient une nouvelle cible thérapeutique potentielle
LMNA gene encodes lamins A and C, two major components of the nuclear lamina, a network of intermediate filaments underlying the inner nuclear membrane. LMNA mutations have been associated with a wide spectrum of human diseases collectively called “laminopathies” affecting one or several tissues, such as muscles. The physiopathological mechanisms underlying laminopathies remain unclear. Given the crucial role of lamins A/C in nuclear architecture and chromatin organization, the “gene regulation” hypothesis have been proposed. It suggests that LMNA mutations could alter in a tissue-specific manner transcription factors and/or genes expression. Moreover, lamins A/C have been described as important regulators in muscle differentiation regulation.To identify potential alterations in signaling pathways regulating muscle differentiation in LMNA-mutated myoblasts, we used a previously described model of conditionally immortalized murine myoblasts and compared gene expression profiles in wild-type and Lmna-/- H-2K myoblasts. We identified two major alterations of the Bone Morphogenetic Protein (BMP) pathway in Lmna-/- myoblasts: Bmp4 downregulation and Smad6 overexpression. We demonstrated that Smad6 overexpression lead to Smad1/5/8 sequestration in the cytoplasm and to the downregulation of their target genes, Id1 and Id2. As a consequence, Lmna-null myoblasts displayed a premature differentiation which could be rescued by downregulating Smad6 expression. Finally, we showed that these defects are relevant for human laminopathies as they are also present in myoblasts from a human patient carrying a LMNA+/Q310X mutation.Taken together, these results provide a potential mechanism for the muscle stem cell exhaustion and muscle atrophy observed in muscle laminopathies and identify a new therapeutical target likely to reverse pathological phenotypes

Les "Bone Morphogenetic Proteins" (BMPs) jouent un rôle clef dans la régulation de cellules précurseurs du muscle prénatal et de cellules souches musculaires adultes dénommées "cellules satellites". Les objectifs principaux de ma thèse étaient d'une part de déterminer si la signalisation BMP joue un rôle pendant la phase de croissance du muscle postnatale/juvénile dépendante des cellules satellites, et d'autre part d'investiguer si cette voie est impliquée dans la maintenance de la masse musculaire squelettique adulte. J'ai trouvé que les composants de cette voie de signalisation sont exprimés dans les cellules satellites de souris néonatales, juvéniles et adultes. Par ailleurs, j'ai utilisé des lignées de souris transgéniques pour surexprimer, de manière conditionnelle, l'inhibiteur Smad6 de la cascade de signalisation BMP dans les cellules satellites ou dans le muscle squelettique. J'ai pu ainsi démontrer que cette signalisation est requise pour une prolifération correcte des cellules satellites et pour leur différentiation en myonuclei, assurant que les fibres musculaires en croissance atteignent une taille finale normale. Par ailleurs, mes travaux révèlent que le nombre final de cellules satellites est établis pendant la phase de croissance postnatale/juvénile et que celle-ci dépend de la cascade de signalisation BMP. Enfin, je fournis des preuves montrant que la signalisation BMP est un puissant signal hypertrophique dans le muscle squelettique adulte et que sa présence est indispensable pour le maintien du tissu musculaire. En résumé, mes résultats de recherche démontrent que les BMPs sont des facteurs de croissance essentiels pour le muscle squelettique postnatal
Bone Morphogenetic Proteins (BMPs), a subfamily of TGF-β growth factors, have been shown to be key signals that regulate embryonic and fetal muscle precursors during prenatal myogenesis, as well as the stem cells of adult muscle, termed ‘satellite cells’, when activated during muscle regeneration. The main aims of my thesis were to elucidate whether BMP signaling plays a role during postnatal/juvenile satellite cell-dependent muscle growth as well as for maintenance of adult muscle mass. I found that components of BMP signaling pathway are expressed in muscle satellite cells of neonatal, juvenile and adult mice. I used transgenic mouse lines to conditionally overexpress the BMP signaling cascade inhibitor Smad6 in muscle satellite cells and in differentiated skeletal muscle. I show that BMP signaling is required for correct proliferation of muscle satellite cells and their differentiation into myonuclei, thereby ensuring that the growing muscle fibers reach the correct final size. Moreover, I demonstrated that the final number of muscle stem cells is established during the postnatal/juvenile growth phase and this also depends on the BMP signaling cascade. Finally, I provide evidence that BMP signaling is a strong hypertrophic signal for the adult skeletal muscle and its presence is indispensable for muscle tissue maintenance. In summary, my findings demonstrate that BMPs are essential growth factors for postnatal skeletal muscle

Les "Bone Morphogenetic Proteins" (BMPs) jouent un rôle clef dans la régulation de cellules précurseurs du muscle prénatal et de cellules souches musculaires adultes dénommées "cellules satellites". Les objectifs principaux de ma thèse étaient d'une part de déterminer si la signalisation BMP joue un rôle pendant la phase de croissance du muscle postnatale/juvénile dépendante des cellules satellites, et d'autre part d'investiguer si cette voie est impliquée dans la maintenance de la masse musculaire squelettique adulte. J'ai trouvé que les composants de cette voie de signalisation sont exprimés dans les cellules satellites de souris néonatales, juvéniles et adultes. Par ailleurs, j'ai utilisé des lignées de souris transgéniques pour surexprimer, de manière conditionnelle, l'inhibiteur Smad6 de la cascade de signalisation BMP dans les cellules satellites ou dans le muscle squelettique. J'ai pu ainsi démontrer que cette signalisation est requise pour une prolifération correcte des cellules satellites et pour leur différentiation en myonuclei, assurant que les fibres musculaires en croissance atteignent une taille finale normale. Par ailleurs, mes travaux révèlent que le nombre final de cellules satellites est établis pendant la phase de croissance postnatale/juvénile et que celle-ci dépend de la cascade de signalisation BMP. Enfin, je fournis des preuves montrant que la signalisation BMP est un puissant signal hypertrophique dans le muscle squelettique adulte et que sa présence est indispensable pour le maintien du tissu musculaire. En résumé, mes résultats de recherche démontrent que les BMPs sont des facteurs de croissance essentiels pour le muscle squelettique postnatal
Bone Morphogenetic Proteins (BMPs), a subfamily of TGF-β growth factors, have been shown to be key signals that regulate embryonic and fetal muscle precursors during prenatal myogenesis, as well as the stem cells of adult muscle, termed ‘satellite cells’, when activated during muscle regeneration. The main aims of my thesis were to elucidate whether BMP signaling plays a role during postnatal/juvenile satellite cell-dependent muscle growth as well as for maintenance of adult muscle mass. I found that components of BMP signaling pathway are expressed in muscle satellite cells of neonatal, juvenile and adult mice. I used transgenic mouse lines to conditionally overexpress the BMP signaling cascade inhibitor Smad6 in muscle satellite cells and in differentiated skeletal muscle. I show that BMP signaling is required for correct proliferation of muscle satellite cells and their differentiation into myonuclei, thereby ensuring that the growing muscle fibers reach the correct final size. Moreover, I demonstrated that the final number of muscle stem cells is established during the postnatal/juvenile growth phase and this also depends on the BMP signaling cascade. Finally, I provide evidence that BMP signaling is a strong hypertrophic signal for the adult skeletal muscle and its presence is indispensable for muscle tissue maintenance. In summary, my findings demonstrate that BMPs are essential growth factors for postnatal skeletal muscle

Le système hématopoïétique est composé de nombreux types cellulaires, tous générés à partir d’un seul type de cellule, la cellule souche hématopoïétique (CSH). Les premières CSH sont produites dans le sac vitellin, puis dans la région aortique. Ce dernier site hématopoïétique est particulièrement important, car c’est là que sont générées les CSH retrouvées chez l’adulte. Les CSH aortiques sont produites à partir de l’endothélium aortique ventral. Les cellules endothéliales (CE) subissent un changement phénotypique radical. Elles perdent leur morphologie et leurs marqueurs endothéliaux, pour acquérir une identité hématopoïétique, et émerger dans la lumière aortique sous forme de clusters hématopoïétiques. Au cours de ma thèse je me suis intéressée aux signaux régulant l’hématopoïèse aortique et la transition endothélio-hématopoïétique. Cela m’a conduit à étudier la voie TGFβ/BMP. L’étude systématique des différents acteurs de cette voie nous a permis de montrer que les Smads 1/5/8 sont activées dans les CE, mais pas dans les clusters hématopoïétiques. Notre hypothèse, basée sur le niveau d’expression des différents récepteurs de cette signalisation, est que les récepteurs Alk1/TgfβR2/Endogline sont responsables de cette activation des Smads, et que leur perte est nécessaire à la production de cellules hématopoïétiques à partir de CE
Hematopoietic system is composed of many cell types, all generated from one cell type, the hematopoietic stem cell (HSC). The firs HSC are produced in the yolk sac, then in the aortic region. The adult HSC are generated in this last hematopoietic site. Aortic HSC are produce from ventral aortic endothelium. The endothelial cells (ECs) undergo a radical modification of their phenotype. They loose theirs endothelial markers, acquire a hematopoietic identity, and emerge in the aortic lumen in the shape of clusters. During my PhD, I study the signaling pathways regulating hematopoiesis and the endothelium to hematopoietic transition. I focus on the TGFβ/BMP pathway. The systematic study of all this pathway actors shows that Smads 1/5/8 are activated in the ECs, but not in hematopoietic clusters. Our hypothesis, based on the level of expression of all TGFβ/BMP receptors, is that Alk1/TgfβR2/Endogline are responsive for the Smads activation, and their loss in necessary to the hematopoietic production in the aorta from ECs

Ce travail suggère l'existence d'une voie Hedgehog (hh) fonctionnelle dans le cerveau adulte. Il décrit l'identification et la localisation des transcrits des gènes codant pour les protéines hh, leur récepteur Ptc/Smo, le facteur de transcription Gli1 et d'autres composantes de la voie dans le cerveau et les tissus périphériques de rat adulte. Des cartographies détaillées de la localisation des cellules exprimant Shh, Ptc et Smo ont été établies dans le cerveau et la moelle épinière de rat adulte ainsi que dans le cervelet postnatal. Leur co-localisation dans un nombre limité d'aires cérébrales suggère que le modèle ternaire Shh/Ptc/Smo classiquement reconnu chez l'embryon n'est pas l'unique modèle de fonctionnement de la voie chez l'adulte, où Shh et Ptc pourraient fonctionner indépendamment de Smo, tandis que Smo lui-même pourrait transmettre l'activité d'un ligand encore non identifié. Dans le cervelet post-natal, mes travaux décrivent l'expression de Shh, Ptc, Smo et Gli1 dans la couche des cellules de Purkinje et dans les zones de prolifération des neuroblastes cérébelleux, suggérant un rôle de la voie Shh dans la prolifération et/ou la différenciation des précurseurs du cervelet ainsi que dans la genèse de médulloblastomes. L'injection intrastriatale de la protéine recombinante myrShhN induit la transcription du récepteur Ptc au niveau de la zone sous- ventriculaire, une aire de neurogenèse persistant chez l'adulte. Ces observations suggèrent un rôle de la voie Shh dans la neurogenèse chez l'adulte. Les gènes codant pour des protéines morphogènes de l'os (BMP), impliquées dans le développement du tube neural durant l'embryogenèse, sont exprimés dans le cerveau adulte suggérant que la voie des BMP pourrait, chez l'adulte, interagir avec la voie Shh, comme précédemment décrit chez l'embryon. La modulation de la transcription du récepteur BMPRII dans un modèle d'ischémie cérébrale supporte l'idée que cette voie est fonctionnelle dans le système nerveux adulte
This work suggests the existence of the functional Hedgehog (hh) signaling pathway in the adult brain. It describes the identification and the localization of the transcripts of genes coding for hh, their receptor Ptc/Smo, the transcription factor Gli1 and other components of the pathway in the brain and peripheral tissues of the adult rat. The detailed mapping of the Shh, Ptc and Smo transcripts was established in the adult brain and spinal cord and in the developing cerebellum. Their colocalization is restricted to a very limited number of adult brain areas, suggesting that a model of the hh signaling in the adult might be different of that previously proposed in the embryo. Ptc could transduce Shh activities in the absence of Smo and Smo itself might bind another not identified yet ligand. The developmental regulation of Shh, Ptc, Smo and Gli1 in the cerebellum suggests a possible role for Shh signaling in the control of various cell populations within the cerebellum, particularly in granule cell precursor proliferation and/or differentiation that might be impaired in proliferative states such as medulloblastomas. The injection of the recombinant protein myrShhN into the adult rat striatum induce a Ptc transcription in the subventricular zone, containing progenitors that can proliferate and differentiate into new neurons and glia in the adult brain. These observations suggest a role for the Shh signaling in the adult neurogenesis. The bone morphogenetic proteins (BMPs) implicated in the neural tube patterning during embryogenesis are expressed also in the adult brain, suggesting that the BMP pathway could interact with the Shh pathway in the adult as in the embryo. The up-regulation of the BMPRII receptor after transient global cerebral ischemia in rat suggests a modulation of the BMP signaling during neuronal plasticity or repair that occur upon brain injury

Les BMPs (Boue Morphogenetic Proteins) sont des morphogènes membres de la superfamille du TGF-[bêta] qui interagissent avec des récepteurs de surface cellulaire à activité sérine/thréonine kinase. L'interaction des BMPs avec ces récepteurs entraîne l'activation d'une cascade de signalisation cellulaire impliquant les facteurs de types R-Smads (Smad1, 5 et 8). La voie de signalisation des BMPs joue des rôles cruciaux dans des processus biologiques tels que l'embryogenèse et l'organogenèse des tissus ainsi que des processus cellulaires tels que la prolifération, la migration et la différenciation cellulaire. De plus, ces derniers semblent aussi impliqués dans les processus de mort cellulaire et dans la tumorigenèse. Malgré un intérêt grandissant pour la signalisation des BMPs, il existe très peu d'études sur les rôles spécifiques joués individuellement par les différents Smads dans la morphogenèse de l'intestin in vivo . Ceci est principalement dû au fait que la délétion classique des différents effecteurs de la voie des BMPs entraîne la mort in utero à cause de multiples défauts dans l'embryogenèse. Le système Cre/loxP, sous le contrôle d'un promoteur tissu spécifique, a été utilisé dans notre laboratoire, dans le but de générer une lignée murine possédant une délétion conditionnelle de l'effecteur Smad5 strictement au niveau de l'épithélium intestinal. Une analyse comparative à l'aide d'un modèle de délétion conditionnelle du récepteur BmpR1a au niveau de l'épithélium intestinal a été effectuée afin de décortiquer spécifiquement le rôle de l'effecteur Smad5 dans le développement de cet organe. Afin de valider les résultats obtenus in vivo nous avons généré un modèle cellulaire nous permettant de mimer l'effet de la délétion de l'effecteur Smad5 à l'aide de la technologie du shRNA.Les résultats obtenus dans les deux modèles suggèrent que Smad5 serait un facteur clé impliqué dans la régulation de la migration cellulaire des entérocytes. En effet, l'invalidation de la voie des BMPs et plus particulièrement de l'effecteur Smad5 dans les souris entraîne une augmentation de la vitesse de migration des cellules le long de l'axe crypte villosité. Ces résultats sont corroborés dans un modèle cellulaire dans lequel l'expression de Smad5 a été inhibée par interférence d'ARN. Dans ce modèle, la migration se fait de façon beaucoup plus compacte en comparaison aux cellules contrôles. L'augmentation de la vitesse de migration cellulaire pourrait être due à un phénomène de relocalisation des protéines de jonctions adhérentes ainsi qu'à une modulation de l'actine filamenteuse. Ce phénomène pourrait faire intervenir les petites protéines G Rho/Rac ainsi que les kinases Src. En plus de l'actine filamenteuse, différentes protéines impliquées dans la formation des complexes de jonctions adhérentes semblent relocalisées dans nos deux modèles (E-cadhérine/[bêta]-caténine). En conclusion, les différents résultats recueillis au cours de mes travaux de maîtrise dans le laboratoire du Dr. Nathalie Perreault nous suggèrent que l'effecteur Smad5 de la voie des BMPs serait un facteur impliqué dans la stabilité des complexes de jonctions adhérentes, régulant ainsi la migration des cellules le long de l'axe crypte villosité.

La spondyloarthrite (SpA) est une maladie inflammatoire chronique fréquente. Chez l'Homme, l'association entre l'allèle HLA-B27 du complexe majeur d'histocompatibilité de classe-I (CMH-I) et le développement de la maladie a été démontrée il y a 50 ans, 70 à 90% des patients atteints de SpA étant porteurs de cet allèle. Cependant, le rôle exact du HLA-B27 dans la physiopathologie de la SpA reste inconnu. Le modèle du rat transgénique pour le HLA-B27 et la β2-microglobuline humaine (hβ2m) (rat B27), qui développe des manifestations similaires à la maladie humaine, a permis d'éclaircir certains aspects de la question. Notamment, l'implication des lymphocytes T (LT) CD4+ dans la SpA a pu être mise en évidence. Chez le rat B27, les LT CD4+ régulateurs (Treg) présentent un déséquilibre de la balance interleukine-10/interleukine-17 (IL-10/IL-17), respectivement anti- et pro- inflammatoires. D'autre part, une expansion de la sous-population des LT CD4+ helper 17 (Th17) pro-inflammatoires, producteurs d'IL-17 est observée aussi bien chez le rat B27 que chez les patients. Dans le but d'étudier les effets non-canoniques du HLA-B27, un modèle de Drosophila melanogaster transgénique pour le HLA-B27 et la hβ2m a été développé et a permis de mettre en évidence qu'une interaction entre le HLA-B27 et des récepteurs de type I de la voie BMP/TGFβ (BMPR1) altérait la formation des veines transversales de l'aile. Dans ce modèle, il a précédemment été montré une interaction entre le HLA-B27 et le récepteur Saxophone (Sax) conduisant à l'augmentation de la signalisation BMP. Notre étude a complété ces résultats en montrant qu'une signalisation aberrante passant par le BMPR1 Baboon (Babo) de la voie de l'activine/TGFβ participait aussi au phénotype anormal induit par l'expression du HLA-B27. Pour tenter d'extrapoler ces résultats à un mécanisme de pathogénicité du HLA-B27 au cours de la SpA, nous avons tout d'abord démontré qu'il existait une interaction spécifique entre HLA-B27 et l'activin receptor-like kinase 2 (ALK2), orthologue de Sax d'une part, mais aussi avec ALK5, le récepteur de type 1 au TGFβ orthologue de Babo dans les lymphocytes de rat B27. L'étude de SMAD2/3, le principal transducteur du signal TGFβ, dans les LT de rats B27 et non transgéniques révèle une phosphorylation basale plus faible et une amplitude de phosphorylation plus forte après stimulation par le TGFβ1. De façon concordante, nous avons observé que certains gènes induits par la signalisation TGFβ et impliqués dans la différenciation des Treg et Th17 (Foxp3, Rorc, Runx1) avaient une expression augmentée dans les LT CD4+ naïfs (Tn) de rat B27. Ensemble, ces résultats indiquent une possible activation précoce de la voie TGFβ dans les Tn des rats B27 suivie d'une boucle de rétrocontrôle négatif. De façon intéressante, le gène Tgfb1 lui-même était diminué. Compte tenu de l'importance du TGFβ1 autocrine produit par les LT pour prévenir l'inflammation chronique, ces observations ouvrent des perspectives pour mieux comprendre le rôle du HLA-B27 dans le développement de la SpA. Nous pourrons en particulier, étudier de façon plus approfondie la réponse des Tn de rats B27 au TGFβ1 par des méthodes multi-omiques (transciptomique, phosphoprotéomique, protéomique...). Enfin, compte tenu du rôle essentiel du TGFβ1 autocrine dans le maintien des profils Treg et Th17, une étude de la plasticité des Treg et Th17 des rats B27 serait pertinentes pour mieux comprendre la physiopathologie de la SpA
Spondyloarthritis (SpA) is a common chronic inflammatory disease. In human, the association between the HLA-B27 allele of the class-I major histocompatibility complex (MHC-I) and the development of this disease was demonstrated 50 years ago, with 70-90% of SpA patients carrying this allele. However, the exact role of HLA-B27 in the pathophysiology of SpA remains unknown. The model of rat transgenic for HLA-B27 and the human β2-microglobulin (hβ2m) (B27 rat), which develops manifestations similar to the human disease, has shed light on certain aspects of the question. In particular, the involvement of CD4+ T lymphocytes in SpA has been demonstrated. In the B27 rat, regulatory CD4+ T lymphocytes (Treg) exhibit an imbalance of the interleukin-10/interleukin-17 (IL-10/IL-17) ratio, which are anti-inflammatory and pro-inflammatory, respectively. On the other hand, an expansion of the sub-population of pro-inflammatory CD4+ T helper 17 (lymphocytes Th17), which produce IL-17, was observed in both B27 rats and SpA patients. To study the non-canonical effects of HLA-B27, a Drosophila melanogaster model transgenic for HLA-B27 and hβ2m was developed and demonstrated that an interaction between HLA-B27 and type I receptors of the BMP/TGFβ pathway (BMPR1s) altered the formation of the wing transverse veins. In this model, an interaction between HLA-B27 and the Saxophone (Sax) receptor has previously been shown to lead to increased BMP signalling. Our study complemented these results by showing that aberrant signaling via the BMPR1 Baboon (Babo) of the activin/TGFβ pathway also contributed to the abnormal phenotype induced by HLA-B27 expression. In an attempt to extrapolate these results to a mechanism of HLA-B27 pathogenicity in SpA, we first demonstrated that there was a specific interaction between HLA-B27 and activin receptor-like kinase 2 (ALK2), the orthologue of Sax, and also with ALK5, the type 1 receptor for TGFβ orthologue of Babo, in rat B27 lymphocytes. Study of SMAD2/3, the main transducer of the TGFβ signal, in T lymphocytes from B27 and nontransgenic rats revealed a lower basal phosphorylation and a higher amplitude of phosphorylation after stimulation by TGFβ1. Concordantly, we observed that several genes induced by TGFβ signaling and involved in Treg and Th17 differentiation (Foxp3, Rorc, Runx1) had increased expression in naive CD4+ T lymphocytes (Tn) from B27 rats. Taken together, these results indicate a possible early activation of the TGFβ pathway in B27 rat Tn followed by a negative feedback loop. Interestingly, the Tgfb1 gene itself was decreased. Given the importance of autocrine TGFβ1 produced by T lymphocytes in preventing chronic inflammation, these observations open up prospects for a better understanding of the role of HLA-B27 in the development of SpA. In particular, we propose to study in greater depth the response of Tn from B27 rats to TGFβ1 using multi-omics methods (transciptomic, phosphoproteomic, proteomic). Finally, given the essential role of autocrine TGFβ1 in the maintenance of Treg and Th17 profiles, a study of the plasticity of Treg and Th17 in B27 rat would be relevant to a better understanding of the pathophysiology of SpA

La spécification de l'axe est un processus essentiel au cours de l'embryogenèse chez les métazoaires. Chez certaines espèces, ce processus est initié par des facteurs maternels localisés dans des régions distinctes de l'œuf non fécondé, tandis que chez d'autres, il dépend entièrement de facteurs zygotiques. Dans l'embryon d'oursin, l'établissement de l'axe dorso-ventral (D/V) dépend de manière critique de l'expression zygotique du ligand TGFβ Nodal. L'expression de nodal est induite de manière ubiquitaire dans l'embryon à 32 cellules et se limite progressivement à l'ectoderme ventral au cours des premiers stades de développement. Cette restriction spatiale précoce de l'expression de nodal dépend du ligand TGFβ exprimé maternellement appelé Panda. En l'absence de Panda, l'expression du nodal n'est plus restreinte et s'étend dans tout l'ectoderme. Ainsi, dans l'embryon d'oursin, l'information sur l'axe D/V est déjà présente dans l'œuf non fécondé grâce à l'ARNm de panda. De plus, le blocage de Panda augmente la gravité des phénotypes causés par le blocage des récepteurs BMP de type I Alk1/2 et Alk3/6, suggérant que Panda pourrait fonctionner comme un ligand pour ces récepteurs BMP. Cependant, la surexpression de l'ARNm de panda n'entraîne pas l'activation de pSmad1/5/8. Par conséquent, le mécanisme par lequel Panda fonctionne reste énigmatique.Au cours de la première partie de ma thèse, j'ai étudié le mécanisme moléculaire par lequel Panda fonctionne pour restreindre l'expression de nodal. Étant donné que Panda n'active pas la signalisation BMP, nous avons émis l'hypothèse que Panda pourrait fonctionner comme Lefty ou Inhibins. Ces derniers antagonisent la signalisation de Nodal en séquestrant un facteur essentiel pour cette voie de signalisation et en régulant à la baisse la boucle d'autorégulation de Nodal. En effet, nous avons pu démontrer que Panda se lie à plusieurs composants de la voie de signalisation de Nodal tels que ACVRII et Cripto. Nous avons découvert que Panda forme également des complexes avec le co-récepteur d'inhibine TBR3, ce qui suggère qu'il pourrait fonctionner de la même manière que Inhibine en séquestrerant ACVRII. À l'aide d'expériences fonctionnelles, nous avons identifié Panda comme un antagoniste du récepteur primaire de type II de Nodal, ACVRII. Nous avons pu montrer que la surexpression de Panda dans l'œuf antagonise la dorsalisation causée par la surexpression d'ACVRII. De plus, nous avons constaté que Panda antagonise également l'activité d'ACVRII dans un essai d'induction d'axe. Alors que la surexpression locale d'ACVRII orientait l'axe D/V et favorisait la signalisation de Nodal et le destin ventral dans près de 100 % des embryons injectés, la co-expression avec Panda bloquait la capacité d'ACVRII à orienter l'axe D/V. L'analyse bioinformatique de la séquence de Panda a révélé que Panda a une séquence très inhabituelle dans la région de liaison à ACVRII. Contrairement à tous les ligands TGFβ qui selient à ACVRII, et qui possèdent une sérine ou une thréonine conservée au milieu de ce motif, Panda et Lefty ont à la place un résidu de proline. Nous avons montré que la conversion de cette proline unique en une sérine inversait le rôle de Panda d'un antagoniste à un agoniste de la signalisation de Nodal. Par conséquent, nous avons attribué l'activité antagoniste de Panda à la présence d'un seul résidu proline dans sa séquence, ce qui confère probablement une activité dominante négative à ce facteur. Ces résultats nous informent sur le mécanisme par lequel Panda fonctionne et de ses implications sur l'évolution des mécanismes de spécification de l'axe D/V.Au cours de la deuxième partie de ma thèse, j'ai caractérisé le rôle d'autres facteurs maternels dans la régulation de l'expression de nodal. Nous avons identifié le récepteur Ret et la voie avale MAPK comme des régulateurs potentiels de l'expression de nodal et la spécification de l'axe D/V
Axis specification is an essential and highly regulated process during embryogenesis in metazoa. In some species, this process is initiated by maternal factors that are localized in distinct regions of the unfertilized egg, while in others, it is entirely dependent on zygotic factors. In the highly regulative sea urchin embryo, establishment of the dorso-ventral (D/V) axis critically depends on the zygotic expression of the TGFβ ligand Nodal. nodal expression is induced ubiquitously in the 32-cell embryo and progressively gets restricted to the presumptive ventral ectoderm during the early stages of development, making nodal the first gene to be asymmetrically expressed along the D/V axis. This early spatial restriction of nodal expression depends on the maternally expressed TGFβ ligand Panda. panda mRNA is asymmetrically deposited in the unfertilized egg in a broad dorsal to ventral gradient. In the absence of Panda, nodal expression is no longer restricted and expands throughout the ectoderm. Thus, in the sea urchin embryo, information on the D/V axis is already present in the unfertilized egg in the form of panda mRNA. Further, blocking Panda increases the severity of the phenotypes caused by blocking the BMP type I receptors Alk1/2 and Alk3/6, suggesting that Panda may function as a ligand for these BMP receptors. However, overexpression of panda mRNA does not result in activation of pSmad1/5/8, the downstream effector of BMP signaling. Therefore, the mechanism by which Panda works remains enigmatic.During the first part of my thesis, I studied the molecular mechanism by which Panda functions to restrict nodal expression. Since Panda does not activate BMP signaling, we hypothesized that Panda may work like Lefty or Inhibins, which antagonize Nodal signaling by sequestering a factor essential for this signaling pathway and by downregulating the Nodal autoregulatory loop. Indeed, using co-immunoprecipitation assays, we could demonstrate that Panda binds to several components of the Nodal pathway such as ACVRII and Cripto. Most interestingly, we found that Panda also forms complexes with the Inhibin co-receptor TBR3, suggesting it might function similar to Inhibins to sequester ACVRII. Using functional experiments, we identified Panda as an antagonist of the primary Nodal type II receptor ACVRII. We could show that overexpression of Panda into the egg antagonizes the dorsalization caused by overexpression of ACVRII. Furthermore, we found that Panda also antagonizes the activity of ACVRII in an axis induction assay. While local overexpression of ACVRII oriented the D/V axis and promoted Nodal signaling and ventral fates in almost 100% of the embryos injected, co-expression with Panda blocked the ability of ACVRII to orient the D/V axis. Bioinformatics analysis of the Panda sequence revealed that Panda has a very unusual sequence in the ACVRII binding region and that unlike all TGFβ ligands that signal through ACVRII, which possess a conserved serine or threonine in the middle of this motif, Panda and Lefty have instead a Proline residue. We have then tested if the antagonistic function of Panda was caused by the presence of this single Proline residue in the ACVRII binding motif. We showed that conversion of this single Proline to a Serine reversed the role of Panda from an antagonist to an agonist of Nodal signaling. Therefore, we have traced the antagonistic activity of Panda to the presence of a single Proline residue in its sequence, which likely confers a dominant negative activity to this factor. These results inform us on the mechanism by which Panda works and have implications on the evolution of the mechanisms of D/V axis specification.During the second part of my thesis, I have characterized the role of other maternal factors in the regulation of nodal expression. We have identified the receptor Ret and the downstream MAPK pathway as potential regulators of nodal expression and D/V axis specification

Introduction : Le cancer du sein est la première cause de décès par cancer chez la femme dans le monde. Il s’agit d’une maladie hétérogène dont il existe plusieurs sous-types moléculaires corrélés au pronostic. Parmi ces différentes entités, le sous-type basal-like présente le pronostic le plus défavorable. Il est caractérisé par une expression accrue de marqueurs de différentiation basale et une instabilité génétique importante, fréquemment due à des altérations de la recombinaison homologue. Il est également enrichi en cellules souches cancéreuses. Ces cellules semblent être impliquées dans les étapes précoces de la carcinogenèse mais également dans la résistance aux traitements cytotoxiques et la rechute. Plusieurs voies de signalisation influencent leur biologie, notamment la voie des « Bone Morphogenetic Proteins » (BMP). Des dérégulations de cette voie ont été mises en évidence dans certaines tumeurs mammaire de sous-type luminal mais son implication dans l’émergence des tumeurs basal-like reste à explorer. Matériels et méthodes : A l’aide d’échantillons primaires et en interrogeant des bases de données publiques, nous avons recherché des anomalies de la voie BMP dans des tumeurs basal-like et des tissus prédisposés mutés pour BRCA1. Nous avons également utilisé la lignée de cellules souches épithéliales mammaires humaines MCF10A afin de modéliser in vitro les processus d’inititation tumorale des cellules souches dans la glande mammaire. Résultats : Nous montrons que l’expression du récepteur BMPR1A et du ligand BMP4 sont dérégulés dans les tumeurs basal-like et les tissus prédisposés. Ces dérégulations entrainent une répression transcriptionnelle de BRCA1 dans notre modèle de cellules souches. Les conséquences fonctionnelles incluent une différentiation préférentielle selon le phénotype basal, une augmentation de la stemness et des altérations de la voie de la recombinaison homologue.Conclusion : Nous suggérons un rôle de l’axe BMP4-BMPR1A dans les étapes précoces de la carcinogénèse de certaines tumeurs mammaires basal-like (i) en soutenant le maintien d’un contingent de cellules souches dans la glande mammaire, (ii) en orientant leur différentiation vers un phénotype basal, (iii) en favorisant l’instabilité génétique nécessaire à leur transformation en cellules souches cancéreuses
Introduction: Breast cancer is the leading cause of cancer death in women worldwide. It is a heterogeneous disease with several molecular subtypes correlated to prognosis. Of these, the basal-like subtype displays the poorest prognosis. It is characterized by increased expression of basal differentiation markers and significant genetic instability, frequently due to alterations in homologous recombination. It is also enriched in cancer stem cells. These cells are thought to be involved in the early stages of carcinogenesis, but also in resistance to cytotoxic treatment and relapse. Several signaling pathways influence their biology, notably the Bone Morphogenetic Protein (BMP) pathway. Dysregulation of this pathway has been demonstrated in certain luminal breast cancers, but its involvement in the emergence of basal-like breast cancers remains to be explored. Materials and methods: Using primary samples and public databases, we searched for BMP pathway abnormalities in basal-like tumors and BRCA1-mutated predisposed tissues. We also used the MCF10A human mammary epithelial stem cell model to explore in vitro the processes of stem cell tumor initiation in the mammary gland. Results: We show that BMPR1A and BMP4 expression is deregulated in basal-like tumors and predisposed tissues. These deregulations lead to transcriptional BRCA1 repression in our stem cell model. Functional consequences include preferential differentiation according to basal phenotype, increased stemness and alterations in the homologous recombination pathway. Conclusion: We suggest a role for the BMP4-BMPR1A axis in the early steps of basal-like carcinogenesis by (i) promoting the maintenance of a stem cell contingent in the mammary gland, (ii) directing their differentiation towards a basal phenotype, (iii) supporting the genetic instability necessary for their transformation into breast cancer stem cells

Anime Studies: Media-Specific Approaches to Neon Genesis Evangelion aims at advancing the study of anime, understood as largely TV-based genre fiction rendered in cel, or cel-look, animation with a strong affinity to participatory cultures and media convergence. Taking Neon Genesis Evangelion (Shin Seiki Evangerion) as a case study, this volume acknowledges anime as a media form with clearly recognizable aesthetic properties, (sub)cultural affordances and situated discourses. First broadcast in Japan in 1995-96, Neon Genesis Evangelion became an epoch-making anime, and later franchise. The initial series used already available conventions, visual resources and narrative tropes typical of anime in general and the mecha (or giant-robot) genre in particular, but at the same time it subverted and reinterpreted them in a highly innovative and as such standard-setting way. Investigating anime through Neon Genesis Evangelion this volume takes a broadly understood media-aesthetic and media-cultural perspective, which pertains to medium in the narrow sense of technology, techniques, materials, and semiotics, but also mediality and mediations related to practices and institutions of production, circulation, and consumption. In no way intended to be exhaustive, this volume attests to the emergence of anime studies as a field in its own right, including but not prioritizing expertise in film studies and Japanese studies, and with due regard to the most widely shared critical publications in Japanese and English language. Thus, the volume provides an introduction to studies of anime, a field that necessarily interrelates media-specific and transmedial aspects. In Anime Studies: Media-Specific Approaches to Neon Genesis Evangelion, anime is addressed from a transnational and transdisciplinary stance. The disciplinary and methodological perspectives taken by the individual chapters range from audio-visual culture, narratology, performance and genre theory to fandom studies and gender studies. In its first part, the book focuses on textual analysis and media form in the narrow sense with regard to filmic media, bank footage, voice acting and musical score, and then it broadens the scope to consider subcultural discourse, franchising, manga and video game adaptations, as well as critical and affective user engagement.

Abstract This chapter explores the relationship between media exposure and vote choice in Indian elections using data from the National Election Study (NES) surveys from 1996 to 2019. It makes five broad observations. First, in the last 2 decades, the Indian electorate has had more exposure to media than ever before. The avenues of exposure have also increased in several ways. Second, electorates with higher media exposure are more likely to vote for the BJP. In that sense, the past two elections were not significantly different. Third, the BJP seems to be reaping the benefits of long-term ideological alignment in Indian politics as well as investments in both its offline and online campaign infrastructure. Fourth, while the BJP is indeed ahead in usage of new technology for the campaign purposes, only some parties have been able to match the BJP’s campaign infrastructure in their respective strongholds. Fifth, the increasing media penetration in the past decade is also marked by social and political polarization in India, which is now getting reflected in declining trust in media sources among Indian citizens.

Nandini Sundar examines the conditions and discursive strategies utilized by the BJP to contribute to building an extensive Adivasi (tribal) voter base that continues to support the BJP despite the party’s alignment with industrialists who displace rural and tribal communities, and whose ruling ideology marginalizes and devalues Adivasis. Narendra Modi’s popularity is no more central to this question than in discussions that revolve around the fatal attraction of the BJP holds to Adivasis and Dalits. Why do Adivasis vote in such large numbers for a party which is clearly aligned with the industrialists who want to displace them; why do Dalits align with a party whose ruling ideology is so clearly holds them in contempt? Sundar analyzes several strategies of incorporating Adivasis into the Hindu nation: Sanskritization, modernization (in the form of schooling), the (anti-Christian) conversion debate, service work, and mass violence and small-scale incidents.

<em>Abstract.</em>—The Charleston Bump is a structural and topographic high on the northern Blake Plateau that overlies a seaward offset of the edge of continental crust. The feature causes the bottom to shoal and deflects the Gulf Stream offshore, causing an intensification of bottom currents. The area has been swept by strong currents since late Cretaceous time, but the strongest currents have occurred in the Neogene (last -25 million years). Nondepositional conditions prevail at present, but erosion of the bottom is checked where the bottom is armored by a hard surficial layer of phosphorite pavement. The phosphorite pavements were formed by re-cementation of eroded residues of phosphorite-rich sediments of early-Neogene age. In some places there are multiple pavements separated by poorly lithified sediments. Submersible observations indicate that the south, or current-facing flank of the Charleston Bump has several deep (>100 m) scour depressions, the southern flanks of which form cliffs characterized by ledges and overhangs. In other areas discrete layers of older Paleogene rocks have been partly eroded away, leaving cliff-like steps of 5 m or more relief. Conglomeratic phosphorite pavement layers up to 1 m thick armor most of the bottom. Where breached by scour, these pavements form both low-relief ledges and rock piles. These features form a reef-like environment of caves and overhangs utilized by wreckfish <em> Polyprion americanus </em>and barrelfish <em> Hyperoglyphe perciformis </em>as shelter from the current and as staging areas to prey on passing schools of squid. Wreckfish and other large fish were often localized in rugged bottom habitat, including caves and other shelter areas. We observed wreckfish darting from shelters to feed on passing schools of squid. Present and past observations, are consistent with the concept that impingement of the Gulf Stream at the Charleston Bump compresses midwater fauna from much thicker water layers, providing food for a flourishing big-fish fauna. During our dives we noted currents often exceeding 1 knot, and ranging to 2.4 knots. Evidence of fossil, manganese-iron-encrusted megaripples suggest even greater current regimes in the past. Investigation of the site of an earlier report of possible freshwater discharge failed to find any evidence of a closed sinkhole or freshwater discharge. Rather, we concluded that the apparent loss of buoyancy experienced by the submarine was probably caused by downward-directed eddy currents generated by currents sweeping across the pavement/void interface of a more than 100-m high cliff 3 km south of the reported location.

Abstract This paper explores the complex relationship between caste and politics in India. It traces the development of caste-based politics and investigates how caste influences people's political choices during elections. The study focuses on four major trends since the 1990s: the decline of the Congress party, the rise of the BJP among Other Backward Classes (OBCs), state-level voting patterns, and the unpredictable nature of consistent vote banks. Additionally, the paper examines the dynamics of caste representation among those in political power in India. It delves into issues related to representation, such as the criteria for entry into politics and the distribution of ministerial power among different castes. The research also explores the complexities of caste mobilization and affirmative action following the Mandal phase. Furthermore, the paper addresses the clientelist nature of caste politics, discussing its impact on democratization and democracy. It also considers the potential for lower strata self-assertion to bring about changes in the caste hierarchy. The paper analyzes the democratic upsurge, ideological enthusiasm, and the subsequent moderation of this trend, highlighting the secularization of caste politics in competitive scenarios.

Abstract The annual profusion of Christmas albums suggests a bottomless appetite for the same dozen or 15 songs done in every conceivable fashion, and a hapless record industry eager to oblige. When in doubt, shake up the backlist, develop a seasonal pun, and leave the rest to nostalgia. It is often noted that most of the good American Christmas songs, beginning with Berlin’s “White Christmas” (1942, not so very long ago) are by Jewish composers. They have secularized the revelry to the point where even unlapsed Catholics must at times struggle to recall that all the fuss commemorates their Savior’s birth and not merely ASCAP and BMI annuities involving sleigh bells, drummer boys, chipmunks, reindeer, chestnuts, Santa, Frosty, and, most crucially, snow—of which there was a dearth in Galilee. Why those songwriters could not bestir themselves to write a decent Hanukkah song is a mystery for the ages. Hath not a Jew snow, snowmen, bells, singing animals, Buddy Rich? Secularist that I am, I don’t need chain-rattling Marley to muster my belief in miracles, for example, the sound of Ella Fitzgerald’s voice in 1960, when she recorded Ella Wishes You a Swinging Christmas, recently reissued by Verve. Her instrument was pearly—perhaps at its apogee— and her time, well, what is there left to say of her time, a musical Greenwich Mean? “Have Yourself a Merry Little Christmas” is near perfect, so near that for the duration of her vocal I am inclined to close the book on singers and concede that paradise is lost.

Vocal fold paralysis affects approximately 7.5 million Americans. Paralysis can be caused by numerous conditions, including head, neck or surgical trauma, endotracheal intubation, neurological conditions, cancer, tumors, just to mention a few. Currently, vocal fold paralysis treatment involves surgery and voice therapy. The vocal folds are composed of a three part material stretched along the larynx, which enables frequency change. Intrinsic laryngeal muscles coordinate the motion of vocal folds during respiration, vocalization, and aid in airway protection. Sensory information is carried by the Superior Laryngeal Nerve (SLN) and the Recurrent Laryngeal Nerve (RLN). Injury to the RLN results in paralysis of all laryngeal muscles excluding the cricothyroid muscle [1]. Although optimal larynx reinnervation has been extensively researched and implemented to improve voice paralysis [2], voice electrotherapy offers an alternative to effectively stimulate the larynx muscles for voice production, breathing and airway protection. One of the main causes of voice disorders is neurological in nature and causes abnormal vocal fold vibration. Of particular importance to this research is paralysis due to RLN injury, which causes acute temporary paralysis [3]. Currently, invasive electrical stimulus is used to activate muscle function; however, abnormal activation of muscle patterns causes muscles to function out of synchronization resulting in low vocal output [4]. For this reason, our work focuses on the development of an effective electromagnetic stimulation system to aid patients with unilateral vocal fold paralysis by stimulating the RLN and in turn reinnervating the adequate laryngeal muscles involved in the vocal fold motion for the purposes of sound vocalization, respiration, and airway protection. So far, a proof of principle has been developed and evaluated to assess the system’s feasibility. The preliminary experiments have been conducted using BioMetal Fibers (BMF) (Toki Corporation, Japan), which are fiber-like solid state actuators designed to contract and extend similar to muscles. BMF contracts when stimulated through a current generated in this case through an electromagnetic field.

A debate among researchers that employee voice and employee silence are distinct constructs is going on for two decades. Furthermore, since 2021 studies are challenging, claimed, and demonstrated through empirical research that voice and silence are independent constructs. In addition, the idea of strategic silence was also presented in the year 2022, supporting this narrative. Hence the main aim of the current study is to provide a holistic picture of all those studies published in the last two decades (2003–2023) claiming voice and silence as unique concepts. For this purpose, the systematic literature review has been developed to know broadly used methodologies, theories, and concepts used in these studies. Furthermore, research gaps have been highlighted where future research is needed. Data were collected through two research databases, Scopus and Web of Science. This paper has expanded the literature in organizing the factual and theoretical knowledge through a systematic literature review for the first time. Thus, it will provide a roadmap for future researchers, human resource practitioners, and managers to understand the concept of voice and silence being unitary constructs and will open future avenues to work on in this sphere.

Experimental data are reported to investigate the dissipation mechanisms that govern two-phase damping and fluid-elastic instability of a single flexible tube in a rigid array. The working fluid is an air-water mixture and the void fraction and interfacial velocity are measured using a bi-optical probe (BOP) positioned upstream of the flexible tube. The present work aims at revisiting the problem of fluid-elastic instability by developping various scaling models of two-phase fluid damping before the onset of instability. For most of the experiments, the measured damping factor was seen to increase with increasing bubble chord length, with decreasing superficial liquid velocity, and with decreasing amplitude of vibration. The Connor’s approach has been generalized to the two-phase flows provided that the reduced velocity is calculated with gas velocity and with mixture density deduced from the local void fraction measured inside the bundle. The collapse of the fluid-elastic data is more satisfactory than when using the Homogeneous Equilibrium Model (HEM). Void fraction, gas velocity, relative velocity, liquid superficial velocity, bubble chord length, vibratory frequency are shown to be relevant parameters to reduce the two-phase damping data. The use of these parameters in non-dimensional numbers such as Capillary number, Reynolds number, pressure ratio, mass ratio leads to helpful observations as well as several promising approaches to the reduction of two-phase damping.

The focus of this paper was to investigate the effects of microvoid content in quartz/BMI laminates on both short and long-term moisture absorption dynamics. The moisture absorption characteristics for the laminates were experimentally obtained by water immersion tests at 25°C of three-ply quartz/BMI samples that contain voids, ranging from 8.6% to 13.7% by volume. The void levels were obtained by conditioning the prepreg at different moisture levels for 48 hours in an environmental chamber before curing in a hot press. The curing process was carried out at 69 kPa, which leads to a more uniform fiber volume fraction for the laminates. Having a constant fiber volume fraction ensures the same amount of fiber-matrix interface present in all the test samples, therefore eliminating the effect of fiber-matrix interface as an experimental variable. It is shown that the presence of microvoids leads to an increased non-Fickian absorption behavior. Hence, the anomalous, non-Fickian absorption parameters are obtained by using a one-dimensional absorption model that accounts for both bound and unbound free water within the laminate. It is shown that the microvoids act as storage sites for moisture which can be described by the one-dimensional, non-Fickian absorption model. Finally, possible relationships between the four absorption model parameters and the process-induced microvoid content are discussed.

Bismaleimide (BMI) resin with Quartz (AQ581) fiber reinforcement is desirable for systems requiring a high glass transition temperature, low dielectric properties, and high laminate mechanical properties. These properties make quartz/BMI an ideal composite material for complex aerospace structures, and are currently being used in various aircraft engine cowlings and radomes. In addition to moisture absorption, quartz/BMI composite laminates are often exposed to different types of hydraulic fluid contaminants, which may lead to anomalous absorption behavior over the service life of the composite structure. Variations in laminate processing conditions, such as prepreg preconditioning and fabrication cure pressure, can have a significant effect on microstructural features of fiber-reinforced composites. Microstructural features, such as fiber volume fraction and void content, can influence mechanical properties and long term absorption of moisture or other liquid contaminants. In this paper, the process-induced microstructure and hydraulic fluid absorption behavior of quartz/BMI laminates are presented. The laminates are fabricated from preconditioned prepregs and cured at different pressures to generate different levels of microvoids, while keeping the fiber volume fraction constant. Location, size and morphology of microvoids are investigated via SEM images obtained from laminates cured at different processing conditions. Composite samples were prepared and fully-immersed in hydraulic fluid at room temperature, and were not subjected to any prior degradation. The laminate samples immersed in hydraulic fluid exhibited clear non-Fickian absorption behavior, which was successfully predicted by the one-dimensional Hindered Diffusion Model (HDM). The degree of non-Fickian absorption behavior, or hindrance coefficient (μ), ranged from 0.30 to 0.72. Model prediction indicates that as the fabrication pressure increased, the maximum fluid content (M∞) decreased considerably. Additionally, a reduction in maximum fluid content was observed when lower relative humidity environments were used for prepreg preconditioning. A discernable difference was not observed in the absorption dynamics when the prepregs were preconditioned at greater than 70% relative humidity.

Dresser Waukesha’s 275GL engine family released in 2009 consists of a 214 liter (13,048 in3) 12 cylinder, and a 285 liter (17,398 in3) 16 cylinder engine derived from Waukesha’s ATGL family. These 1000 RPM engines are typically used in mechanical drive applications for natural gas compression at 2500 to 3300 kWb (3400–4500 bhp). Through market analysis and voice of customer (VOC) interviews, it was determined that lower Oxides of Nitrogen (NOx) output is essential for future engine sales in North America. Meeting this requirement with a minimal impact to fuel efficiency, fuel tolerance, turndown range, and altitude capability were also desired. To meet the lower NOx requirement, combustion was improved using Computational Fluid Dynamics (CFD) modeling and Design of Experiments (DoE) tools. To assure the low NOx emissions were maintained throughout the desired operating regime, an NOx sensor based air/fuel ratio control system was developed. This new NOx control capability is an enhancement to the Dresser Waukesha ESM™ engine control system. The result is an engine family that consistently meets stringent 0.5 g/bhp-hr NOx levels while maintaining fuel efficiency, fuel tolerance, and turndown range. Reduced combustion pressure in the 275GL Low NOx engine has also allowed a power increase over the original 275GL engine. This paper will discuss the testing and results of this development.

The war in Ukraine has had a serious impact on Bulgaria, both politically and economically. Bulgaria shares historically strong ties with Russia, and at least a third, if not half, of Bulgarians harbour deeply rooted pro-Russian sentiments. Although Sofia eventually supported sanctions against Moscow, sent humanitarian and military aid to Kyiv, and accepted Ukrainian refugees, key political actors in Bulgaria have vehemently opposed such decisions. Particular opposition has come from the Bulgarian Socialist Party (BSP), the successor to the communist party, Bulgaria’s incumbent president, and at least one populist Radical Right party—Vazrazhdane or Revival—whose support has grown significantly since the start of the war. In the process, Revival and its leaders have managed to capitalize on the nationalist vote and pro-Russian attitudes in the country, almost entirely wiping out voter support for the more established Far Right parties.

Banco de la República is celebrating its 100th anniversary in 2023. This is a very significant anniversary and one that provides an opportunity to highlight the contribution the Bank has made to the country’s development. Its track record as guarantor of monetary stability has established it as the one independent state institution that generates the greatest confidence among Colombians due to its transparency, management capabilities, and effective compliance with the central banking and cultural responsibilities entrusted to it by the Constitution and the Law. On a date as important as this, the Board of Directors of Banco de la República (BDBR) pays tribute to the generations of governors and officers whose commitment and dedication have contributed to the growth of this institution.1 Banco de la República’s mandate was confirmed in the National Constitutional Assembly of 1991 where the citizens had the opportunity to elect the seventy people who would have the task of drafting a new constitution. The leaders of the three political movements with the most votes were elected as chairs to the Assembly, and this tripartite presidency reflected the plurality and the need for consensus among the different political groups to move the reform forward. Among the issues considered, the National Constitutional Assembly gave special importance to monetary stability. That is why they decided to include central banking and to provide Banco de la República with the necessary autonomy to use the instruments for which they are responsible without interference from other authorities. The constituent members understood that ensuring price stability is a state duty and that the entity responsible for this task must be enshrined in the Constitution and have the technical capability and institutional autonomy necessary to adopt the decisions they deem appropriate to achieve this fundamental objective in coordination with the general economic policy. In particular, Article 373 established that “the State, through Banco de la República, shall ensure the maintenance of the purchasing power of the currency,” a provision that coincided with the central banking system adopted by countries that have been successful in controlling inflation. In 1999, in Ruling 481, the Constitutional Court stated that “the duty to maintain the purchasing power of the currency applies to not only the monetary, credit, and exchange authority, i.e., the Board of Banco de la República, but also those who have responsibilities in the formulation and implementation of the general economic policy of the country” and that “the basic constitutional purpose of Banco de la República is the protection of a sound currency. However, this authority must take the other economic objectives of state intervention such as full employment into consideration in their decisions since these functions must be coordinated with the general economic policy.” The reforms to Banco de la República agreed upon in the Constitutional Assembly of 1991 and in Act 31/1992 can be summarized in the following aspects: i) the Bank was assigned a specific mandate: to maintain the purchasing power of the currency in coordination with the general economic policy; ii) the BDBR was designatedas the monetary, foreign exchange, and credit authority; iii) the Bank and its Board of Directors were granted a significant degree of independence from the government; iv) the Bank was prohibited from granting credit to the private sector except in the case of the financial sector; v) established that in order to grant credit to the government, the unanimous vote of its Board of Directors was required except in the case of open market transactions; vi) determined that the legislature may, in no case, order credit quotas in favor of the State or individuals; vii) Congress was appointed, on behalf of society, as the main addressee of the Bank’s reporting exercise; and viii) the responsibility for inspection, surveillance, and control over Banco de la República was delegated to the President of the Republic. The members of the National Constitutional Assembly clearly understood that the benefits of low and stable inflation extend to the whole of society and contribute mto the smooth functioning of the economic system. Among the most important of these is that low inflation promotes the efficient use of productive resources by allowing relative prices to better guide the allocation of resources since this promotes economic growth and increases the welfare of the population. Likewise, low inflation reduces uncertainty about the expected return on investment and future asset prices. This increases the confidence of economic agents, facilitates long-term financing, and stimulates investment. Since the low-income population is unable to protect itself from inflation by diversifying its assets, and a high proportion of its income is concentrated in the purchase of food and other basic goods that are generally the most affected by inflationary shocks, low inflation avoids arbitrary redistribution of income and wealth.2 Moreover, low inflation facilitates wage negotiations, creates a good labor climate, and reduces the volatility of employment levels. Finally, low inflation helps to make the tax system more transparent and equitable by avoiding the distortions that inflation introduces into the value of assets and income that make up the tax base. From the monetary authority’s point of view, one of the most relevant benefits of low inflation is the credibility that economic agents acquire in inflation targeting, which turns it into an effective nominal anchor on price levels. Upon receiving its mandate, and using its autonomy, Banco de la República began to announce specific annual inflation targets as of 1992. Although the proposed inflation targets were not met precisely during this first stage, a downward trend in inflation was achieved that took it from 32.4% in 1990 to 16.7% in 1998. At that time, the exchange rate was kept within a band. This limited the effectiveness of monetary policy, which simultaneously sought to meet an inflation target and an exchange rate target. The Asian crisis spread to emerging economies and significantly affected the Colombian economy. The exchange rate came under strong pressure to depreciate as access to foreign financing was cut off under conditions of a high foreign imbalance. This, together with the lack of exchange rate flexibility, prevented a countercyclical monetary policy and led to a 4.2% contraction in GDP that year. In this context of economic slowdown, annual inflation fell to 9.2% at the end of 1999, thus falling below the 15% target set for that year. This episode fully revealed how costly it could be, in terms of economic activity, to have inflation and exchange rate targets simultaneously. Towards the end of 1999, Banco de la República announced the adoption of a new monetary policy regime called the Inflation Targeting Plan. This regime, known internationally as ‘Inflation Targeting,’ has been gaining increasing acceptance in developed countries, having been adopted in 1991 by New Zealand, Canada, and England, among others, and has achieved significant advances in the management of inflation without incurring costs in terms of economic activity. In Latin America, Brazil and Chile also adopted it in 1999. In the case of Colombia, the last remaining requirement to be fulfilled in order to adopt said policy was exchange rate flexibility. This was realized around September 1999, when the BDBR decided to abandon the exchange-rate bands to allow the exchange rate to be freely determined in the market.Consistent with the constitutional mandate, the fundamental objective of this new policy approach was “the achievement of an inflation target that contributes to maintaining output growth around its potential.”3 This potential capacity was understood as the GDP growth that the economy can obtain if it fully utilizes its productive resources. To meet this objective, monetary policy must of necessity play a countercyclical role in the economy. This is because when economic activity is below its potential and there are idle resources, the monetary authority can reduce the interest rate in the absence of inflationary pressure to stimulate the economy and, when output exceeds its potential capacity, raise it. This policy principle, which is immersed in the models for guiding the monetary policy stance, makes the following two objectives fully compatible in the medium term: meeting the inflation target and achieving a level of economic activity that is consistent with its productive capacity. To achieve this purpose, the inflation targeting system uses the money market interest rate (at which the central bank supplies primary liquidity to commercial banks) as the primary policy instrument. This replaced the quantity of money as an intermediate monetary policy target that Banco de la República, like several other central banks, had used for a long time. In the case of Colombia, the objective of the new monetary policy approach implied, in practical terms, that the recovery of the economy after the 1999 contraction should be achieved while complying with the decreasing inflation targets established by the BDBR. The accomplishment of this purpose was remarkable. In the first half of the first decade of the 2000s, economic activity recovered significantly and reached a growth rate of 6.8% in 2006. Meanwhile, inflation gradually declined in line with inflation targets. That was how the inflation rate went from 9.2% in 1999 to 4.5% in 2006, thus meeting the inflation target established for that year while GDP reached its potential level. After this balance was achieved in 2006, inflation rebounded to 5.7% in 2007, above the 4.0% target for that year due to the fact that the 7.5% GDP growth exceeded the potential capacity of the economy.4 After proving the effectiveness of the inflation targeting system in its first years of operation, this policy regime continued to consolidate as the BDBR and the technical staff gained experience in its management and state-of-the-art economic models were incorporated to diagnose the present and future state of the economy and to assess the persistence of inflation deviations and expectations with respect to the inflation target. Beginning in 2010, the BDBR established the long-term 3.0% annual inflation target, which remains in effect today. Lower inflation has contributed to making the macroeconomic environment more stable, and this has favored sustained economic growth, financial stability, capital market development, and the functioning of payment systems. As a result, reductions in the inflationary risk premia and lower TES and credit interest rates were achieved. At the same time, the duration of public domestic debt increased significantly going from 2.27 years in December 2002 to 5.86 years in December 2022, and financial deepening, measured as the level of the portfolio as a percentage of GDP, went from around 20% in the mid-1990s to values above 45% in recent years in a healthy context for credit institutions.Having been granted autonomy by the Constitution to fulfill the mandate of preserving the purchasing power of the currency, the tangible achievements made by Banco de la República in managing inflation together with the significant benefits derived from the process of bringing inflation to its long-term target, make the BDBR’s current challenge to return inflation to the 3.0% target even more demanding and pressing. As is well known, starting in 2021, and especially in 2022, inflation in Colombia once again became a serious economic problem with high welfare costs. The inflationary phenomenon has not been exclusive to Colombia and many other developed and emerging countries have seen their inflation rates move away from the targets proposed by their central banks.5 The reasons for this phenomenon have been analyzed in recent Reports to Congress, and this new edition delves deeper into the subject with updated information. The solid institutional and technical base that supports the inflation targeting approach under which the monetary policy strategy operates gives the BDBR the necessary elements to face this difficult challenge with confidence. In this regard, the BDBR reiterated its commitment to the 3.0% inflation target in its November 25 communiqué and expects it to be reached by the end of 2024.6 Monetary policy will continue to focus on meeting this objective while ensuring the sustainability of economic activity, as mandated by the Constitution. Analyst surveys done in March showed a significant increase (from 32.3% in January to 48.5% in March) in the percentage of responses placing inflation expectations two years or more ahead in a range between 3.0% and 4.0%. This is a clear indication of the recovery of credibility in the medium-term inflation target and is consistent with the BDBR’s announcement made in November 2022. The moderation of the upward trend in inflation seen in January, and especially in February, will help to reinforce this revision of inflation expectations and will help to meet the proposed targets. After reaching 5.6% at the end of 2021, inflation maintained an upward trend throughout 2022 due to inflationary pressures from both external sources, associated with the aftermath of the pandemic and the consequences of the war in Ukraine, and domestic sources, resulting from: strengthening of local demand; price indexation processes stimulated by the increase in inflation expectations; the impact on food production caused by the mid-2021 strike; and the pass-through of depreciation to prices. The 10% increase in the minimum wage in 2021 and the 16% increase in 2022, both of which exceeded the actual inflation and the increase in productivity, accentuated the indexation processes by establishing a high nominal adjustment benchmark. Thus, total inflation went to 13.1% by the end of 2022. The annual change in food prices, which went from 17.2% to 27.8% between those two years, was the most influential factor in the surge in the Consumer Price Index (CPI). Another segment that contributed significantly to price increases was regulated products, which saw the annual change go from 7.1% in December 2021 to 11.8% by the end of 2022. The measure of core inflation excluding food and regulated items, in turn, went from 2.5% to 9.5% between the end of 2021 and the end of 2022. The substantial increase in core inflation shows that inflationary pressure has spread to most of the items in the household basket, which is characteristic of inflationary processes with generalized price indexation as is the case in Colombia. Monetary policy began to react early to this inflationary pressure. Thus, starting with its September 2021 session, the BDBR began a progressive change in the monetary policy stance moving away from the historical low of a 1.75% policy rate that had intended to stimulate the recovery of the economy. This adjustment process continued without interruption throughout 2022 and into the beginning of 2023 when the monetary policy rate reached 12.75% last January, thus accumulating an increase of 11 percentage points (pp). The public and the markets have been surprised that inflation continued to rise despite significant interest rate increases. However, as the BDBR has explained in its various communiqués, monetary policy works with a lag. Just as in 2022 economic activity recovered to a level above the pre-pandemic level, driven, along with other factors, by the monetary stimulus granted during the pandemic period and subsequent months, so too the effects of the current restrictive monetary policy will gradually take effect. This will allow us to expect the inflation rate to converge to 3.0% by the end of 2024 as is the BDBR’s purpose.Inflation results for January and February of this year showed declining marginal increases (13 bp and 3 bp respectively) compared to the change seen in December (59 bp). This suggests that a turning point in the inflation trend is approaching. In other Latin American countries such as Chile, Brazil, Perú, and Mexico, inflation has peaked and has begun to decline slowly, albeit with some ups and downs. It is to be expected that a similar process will take place in Colombia in the coming months. The expected decline in inflation in 2023 will be due, along with other factors, to lower cost pressure from abroad as a result of the gradual normalization of supply chains, the overcoming of supply shocks caused by the weather, and road blockades in previous years. This will be reflected in lower adjustments in food prices, as has already been seen in the first two months of the year and, of course, the lagged effect of monetary policy. The process of inflation convergence to the target will be gradual and will extend beyond 2023. This process will be facilitated if devaluation pressure is reversed. To this end, it is essential to continue consolidating fiscal sustainability and avoid messages on different public policy fronts that generate uncertainty and distrust. 1 This Report to Congress includes Box 1, which summarizes the trajectory of Banco de la República over the past 100 years. In addition, under the Bank’s auspices, several books that delve into various aspects of the history of this institution have been published in recent years. See, for example: Historia del Banco de la República 1923-2015; Tres banqueros centrales; Junta Directiva del Banco de la República: grandes episodios en 30 años de historia; Banco de la República: 90 años de la banca central en Colombia. 2 This is why lower inflation has been reflected in a reduction of income inequality as measured by the Gini coefficient that went from 58.7 in 1998 to 51.3 in the year prior to the pandemic. 3 See Gómez Javier, Uribe José Darío, Vargas Hernando (2002). “The Implementation of Inflation Targeting in Colombia”. Borradores de Economía, No. 202, March, available at: https://repositorio.banrep.gov.co/handle/20.500.12134/5220 4 See López-Enciso Enrique A.; Vargas-Herrera Hernando and Rodríguez-Niño Norberto (2016). “The inflation targeting strategy in Colombia. An historical view.” Borradores de Economía, No. 952. https://repositorio.banrep.gov.co/handle/20.500.12134/6263 5 According to the IMF, the percentage change in consumer prices between 2021 and 2022 went from 3.1% to 7.3% for advanced economies, and from 5.9% to 9.9% for emerging market and developing economies. 6 https://www.banrep.gov.co/es/noticias/junta-directiva-banco-republica-reitera-meta-inflacion-3

In the second quarter, annual inflation (9.67%), the technical staff’s projections and its expectations continued to increase, remaining above the target. International cost shocks, accentuated by Russia's invasion of Ukraine, have been more persistent than projected, thus contributing to higher inflation. The effects of indexation, higher than estimated excess demand, a tighter labor market, inflation expectations that continue to rise and currently exceed 3%, and the exchange rate pressures add to those described above. High core inflation measures as well as in the producer price index (PPI) across all baskets confirm a significant spread in price increases. Compared to estimates presented in April, the new forecast trajectory for headline and core inflation increased. This was partly the result of greater exchange rate pressure on prices, and a larger output gap, which is expected to remain positive for the remainder of 2022 and which is estimated to close towards yearend 2023. In addition, these trends take into account higher inflation rate indexation, more persistent above-target inflation expectations, a quickening of domestic fuel price increases due to the correction of lags versus the parity price and higher international oil price forecasts. The forecast supposes a good domestic supply of perishable foods, although it also considers that international prices of processed foods will remain high. In terms of the goods sub-basket, the end of the national health emergency implies a reversal of the value-added tax (VAT) refund applied to health and personal hygiene products, resulting in increases in the prices of these goods. Alternatively, the monetary policy adjustment process and the moderation of external shocks would help inflation and its expectations to begin to decrease over time and resume their alignment with the target. Thus, the new projection suggests that inflation could remain high for the second half of 2022, closing at 9.7%. However, it would begin to fall during 2023, closing the year at 5.7%. These forecasts are subject to significant uncertainty, especially regarding the future behavior of external cost shocks, the degree of indexation of nominal contracts and decisions made regarding the domestic price of fuels. Economic activity continues to outperform expectations, and the technical staff’s growth projections for 2022 have been revised upwards from 5% to 6.9%. The new forecasts suggest higher output levels that would continue to exceed the economy’s productive capacity for the remainder of 2022. Economic growth during the first quarter was above that estimated in April, while economic activity indicators for the second quarter suggest that the GDP could be expected to remain high, potentially above that of the first quarter. Domestic demand is expected to maintain a positive dynamic, in particular, due to the household consumption quarterly growth, as suggested by vehicle registrations, retail sales, credit card purchases and consumer loan disbursement figures. A slowdown in the machinery and equipment imports from the levels observed in March contrasts with the positive performance of sales and housing construction licenses, which indicates an investment level similar to that registered for the first three months of the year. International trade data suggests the trade deficit would be reduced as a consequence of import levels that would be lesser than those observed in the first quarter, and stable export levels. For the remainder of the year and 2023, a deceleration in consumption is expected from the high levels seen during the first half of the year, partially as a result of lower repressed demand, tighter domestic financial conditions and household available income deterioration due to increased inflation. Investment is expected to continue its slow recovery while remaining below pre-pandemic levels. The trade deficit is expected to tighten due to projected lower domestic demand dynamics, and high prices of oil and other basic goods exported by the country. Given the above, economic growth in the second quarter of 2022 would be 11.5%, and for 2022 and 2023 an annual growth of 6.9% and 1.1% is expected, respectively. Currently, and for the remainder of 2022, the output gap would be positive and greater than that estimated in April, and prices would be affected by demand pressures. These projections continue to be affected by significant uncertainty associated with global political tensions, the expected adjustment of monetary policy in developed countries, external demand behavior, changes in country risk outlook, and the future developments in domestic fiscal policy, among others. The high inflation levels and respective expectations, which exceed the target of the world's main central banks, largely explain the observed and anticipated increase in their monetary policy interest rates. This environment has tempered the growth forecast for external demand. Disruptions in value chains, rising international food and energy prices, and expansionary monetary and fiscal policies have contributed to the rise in inflation and above-target expectations seen by several of Colombia’s main trading partners. These cost and price shocks, heightened by the effects of Russia's invasion of Ukraine, have been more prevalent than expected and have taken place within a set of output and employment recovery, variables that in some countries currently equal or exceed their projected long-term levels. In response, the U.S. Federal Reserve accelerated the pace of the benchmark interest rate increase and rapidly reduced liquidity levels in the money market. Financial market actors expect this behavior to continue and, consequently, significantly increase their expectations of the average path of the Fed's benchmark interest rate. In this setting, the U.S. dollar appreciated versus the peso in the second quarter and emerging market risk measures increased, a behavior that intensified for Colombia. Given the aforementioned, for the remainder of 2022 and 2023, the Bank's technical staff increased the forecast trajectory for the Fed's interest rate and reduced the country's external demand growth forecast. The projected oil price was revised upward over the forecast horizon, specifically due to greater supply restrictions and the interruption of hydrocarbon trade between the European Union and Russia. Global geopolitical tensions, a tightening of monetary policy in developed economies, the increase in risk perception for emerging markets and the macroeconomic imbalances in the country explain the increase in the projected trajectory of the risk premium, its trend level and the neutral real interest rate1. Uncertainty about external forecasts and their consequent impact on the country's macroeconomic scenario remains high, given the unpredictable evolution of the conflict between Russia and Ukraine, geopolitical tensions, the degree of the global economic slowdown and the effect the response to recent outbreaks of the pandemic in some Asian countries may have on the world economy. This macroeconomic scenario that includes high inflation, inflation forecasts, and expectations above 3% and a positive output gap suggests the need for a contractionary monetary policy that mitigates the risk of the persistent unanchoring of inflation expectations. In contrast to the forecasts of the April report, the increase in the risk premium trend implies a higher neutral real interest rate and a greater prevailing monetary stimulus than previously estimated. For its part, domestic demand has been more dynamic, with a higher observed and expected output level that exceeds the economy’s productive capacity. The surprising accelerations in the headline and core inflation reflect stronger and more persistent external shocks, which, in combination with the strength of aggregate demand, indexation, higher inflation expectations and exchange rate pressures, explain the upward projected inflation trajectory at levels that exceed the target over the next two years. This is corroborated by the inflation expectations of economic analysts and those derived from the public debt market, which continued to climb and currently exceed 3%. All of the above increase the risk of unanchoring inflation expectations and could generate widespread indexation processes that may push inflation away from the target for longer. This new macroeconomic scenario suggests that the interest rate adjustment should continue towards a contractionary monetary policy landscape. 1.2. Monetary policy decision Banco de la República’s Board of Directors (BDBR), at its meetings in June and July 2022, decided to continue adjusting its monetary policy. At its June meeting, the BDBR decided to increase the monetary policy rate by 150 basis points (b.p.) and its July meeting by majority vote, on a 150 b.p. increase thereof at its July meeting. Consequently, the monetary policy interest rate currently stands at 9.0% . 1 The neutral real interest rate refers to the real interest rate level that is neither stimulative nor contractionary for aggregate demand and, therefore, does not generate pressures that lead to the close of the output gap. In a small, open economy like Colombia, this rate depends on the external neutral real interest rate, medium-term components of the country risk premium, and expected depreciation. Box 1: A Weekly Indicator of Economic Activity for Colombia Juan Pablo Cote Carlos Daniel Rojas Nicol Rodriguez Box 2: Common Inflationary Trends in Colombia Carlos D. Rojas-Martínez Nicolás Martínez-Cortés Franky Juliano Galeano-Ramírez Box 3: Shock Decomposition of 2021 Forecast Errors Nicolás Moreno Arias