The Genoese Citizenship of Carlo I Tocco of December 2, 1389 (II)

The Genoese citizenship, granted to Carlo I Tocco and his regent mother Magdalene by the authorities of the Republic of Genova (December 2, 1389) is a document the existence of which is widely accepted in the scholarly circles despite the fact that the details of its content have still remained largely unknown. Attempting to contribute to a better understanding of the circumstances under which the grant was issued, the first part of this paper brings the transcription of the entire document as well as an analysis of its political and legal context. The paper's second part deals with the document's paleographic, diplomatic, and sigillographic features, as well as with its prosopographic and topographic details

Familiares, Egregii and Homines Despoti Nonnulli: The Retinue on the Hungarian Estates of Despot George Branković and its Social Capacity (1427-1456)

Las propiedades que los gobernantes serbios tardomedievales tenían en el reino de Hungría no son desconocidas para las historiografías nacionales modernas de Europa Central. Estas propiedades se encontraban principalmente en el sur, este y noreste de ese país y fueron inicialmente concedidas por el rey húngaro (y soberano del Sacro Imperio Romano Germánico) Segismundo de Luxemburgo. Este artículo explora las capacidades sociales del entorno “cosmopolita” del déspota serbio George Branković en sus dominios en Hungría (1427-1456) y considera cómo tales capacidades impulsaron el avance social de estos hombres pero también la interacción del déspota (escasa integración) con sus entornos húngaros, haciendo particular hincapié en sus relaciones con la corte regia. En este grupo híbrido “cosmopolita” y socialmente diversificado, se advierte cómo sus avances pudieron estar anclados en sus redes familiares, el conocimiento personal y sus habilidades o servicio militar y cortesano. No obstante, su característica más significativa era la lealtad extraordinaria, que todos los hombres y delegados del déspota –independientemente de su origen social, étnico o religioso– mostraron hacia su señor feudal. Por medio de ese recurso confirmaron sus patrimonios, así como lograron avances posteriores en su estatus, modificando la relación cercana con el déspota y provocando el cambio de una nobleza antiguamente marginalizada desde el punto de vista territorial hacia una nueva nobleza feudal. Las propiedadesque los gobernantes serbios tardomedievales tenían en el reino de Hungría no son desconocidas para las historiografías nacionales modernas de Europa Central. Estas propiedades se encontraban principalmente en el sur, este y noreste de ese país y fueron inicialmente concedidas por el rey húngaro (y soberano del Sacro imperio Romano Germánico) Segismundo de Luxemburgo. este artículo explora las capacidades sociales del entorno “cosmopolita” del déspota serbio George Branković en sus dominios en Hungría (1427-1456) y considera cómo tales capacida-des impulsaron el avance social de estos hombres pero también la interacción del dés-pota (escasa integración) con sus entornos húngaros, haciendo particular hincapié en sus relaciones con la corte regia. en este grupo híbrido “cosmopolita” y socialmente diversificado, se advierte cómo sus avances pudieron estar anclados en sus redes fa-miliares, el conocimiento personal y sus habilidades o servicio militar y cortesano. No obstante, su característica más significativa era la lealtad extraordinaria, que todos los hombres y delegados del déspota –independientemente de su origen social, étnico o religioso– mostraron hacia su señor feudal. Por medio de ese recurso confirmaron sus patrimonios, así como lograron avances posteriores en su estatus, modificando la relación cercana con el déspota y provocando el cambio de una nobleza antiguamente marginalizada desde el punto de vista territorial hacia una nueva nobleza feudal. The estates which late medieval Serbian rulers held in the Kingdom of Hungary are not unknown to the modern national historiographies of Central Europe. These estates were cored in southern, eastern and north-eastern Hungary, initially granted by Hungarian King (and Holy Roman emperor) Sigismund of Luxembourg. The paper explores the social capacities of the “cosmopolitan” entourage of Serbian Despot George Branković on his domains in Hungary (1427-1456) and seeks an answer to how these capacities operated in prompting these men’s social advancement but also Despot’s interaction (hardly integration) with his surroundings in Hungary, with a particular focus on his relations with the royal court. In this hybrid “cosmopolitan” and socially diversified group, one can notice as their advancement may have been grafted upon their familial networks, personal knowledge and skills or military and courtly service, but its most significant feature was an extraordinary loyalty which all Despot’s men and proxies –regardless of their social, ethnic of religious background– showed to their feudal lord. it is through this concept that they had their personal assets confirmed, as well as their further status advancements, close relationship with the Despot and change from an ‘olden’ territorial marginalised into the new feudal nobility

Restoration, Reconstruction and Union: memories of home in the stratiot poetry of Antonio Molino

The paper explores the notion of home in the stratiot poetry authored by 16th-century Venetian comedy author and composer Antonio Molino. Rooted in the life of the stratiots and their struggles against the Ottomans, this poetry allegedly reflects the diasporic memory of Greek stratiots, although it is apparently framed by the genre and preferences of Molino’s theatre audience. By analysing the memoryscape of notions of home which Molino linked to the Greek stratiots of his time, the paper reveals that his poetry projects, in fact, were the more tangible political ambitions of the Republic of Venice to convert the stratiots from Orthodox Christianity to Roman Catholicism, reinforce their Venetian identity and use their memory in its own aspiration to the Byzantine imperial legacy – all highly topical on the eve of the Venetian conflict with the Ottomans over Cyprus (1571–1573)

N-Methyl D-Aspartate Receptor Antagonist Kynurenic Acid Affects Human Cortical Development

Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan degradation, acts as an endogenous N-methyl-D-aspartate receptor (NMDAR) antagonist. Elevated levels of KYNA have been observed in pregnant women after viral infections and are considered to play a role in neurodevelopmental disorders. However, the consequences of KYNA-induced NMDAR blockade in human cortical development still remain elusive. To study the potential impact of KYNA on human neurodevelopment, we used an in vitro system of multipotent cortical progenitors, i.e., radial glia cells (RGCs), enriched from human cerebral cortex at mid-gestation (16-19 gestational weeks). KYNA treatment significantly decreased RGCs proliferation and survival by antagonizing NMDAR. This alteration resulted in a reduced number of cortical progenitors and neurons while number and activation of astrocytes increased. KYNA treatment reduced differentiation of RGCs into GABAergic neurons, while differentiation into glutamatergic neurons was relatively spared. Furthermore, in mixed cortical cultures KYNA triggered an inflammatory response as evidenced by increased levels of the pro-inflammatory cytokine IL-6. In conclusion, elevated levels of KYNA play a significant role in human RGC fate determination by antagonizing NMDARs and by activating an inflammatory response. The altered cell composition observed in cell culture following exposure to elevated KYNA levels suggests a mechanism for impairment of cortical circuitry formation in the fetal brain after viral infection, as seen in neurodevelopmental disorders such as schizophrenia

Sonic hedgehog promotes generation and maintenance of human forebrain Olig2 progenitors

Function of oligodendrocytes (OLs), myelin forming cells in the CNS, is disrupted in demyelinating diseases such as periventricular leukomalacia or multiple sclerosis. It is, thus, important to better understand factors that can affect generation or differentiation of human OLs. In rodents, Sonic hedgehog (Shh) is influencing expression of Olig2, a helix-loop-helix transcription factor required for development of OLs. In humans, Olig2 is present in cortical progenitors at midgestation, however the role of Shh in the specification of human OLs, including Olig2 positive (Olig2+) progenitors, is not fully understood. Here we studied in vitro effects of Shh signaling on proliferation and specification of human cortical Olig2+ progenitors at midgestation. First, we established that the spatial pattern of Olig2 expression in the human developing CNS, described on cryosections, was preserved in mixed and enriched radial glia cell (RGC) cultures. Next, we demonstrated that in vitro treatment with Shh induced an increase in the number of Olig2+ progenitors. Shh treatment increased the density of early oligodendrocyte progenitors (OPCs) at the expense of RGC, while the number of late OPCs, did not change. However, inhibition of endogenous Shh with cyclopamine did not reduce the density of Olig2+ cells, implying the presence of an additional Shh-independent mechanism for OLs generation in vitro. These results suggest that the primary role of Shh signaling in the human dorsal oligodendrogenesis is the expansion and specification of multipotent radial glia progenitors into Olig2+ early OPCs. These results obtained in vitro are relevant to understand primary myelination during CNS development, as well as remyelination in demyelinating diseases

Oligodendrocyte Development and the Onset of Myelination in the Human Fetal Brain

Oligodendrocytes are cells that myelinate axons, providing saltatory conduction of action potentials and proper function of the central nervous system. Myelination begins prenatally in the human, and the sequence of oligodendrocyte development and the onset of myelination are not thoroughly investigated. This knowledge is important to better understand human diseases, such as periventricular leukomalacia, one of the leading causes of motor deficit in premature babies, and demyelinating disorders such as multiple sclerosis (MS). In this review we discuss the spatial and temporal progression of oligodendrocyte lineage characterized by the expression of specific markers and transcription factors in the human fetal brain from the early embryonic period (5 gestational weeks, gw) until midgestation (24 gw). Our in vitro evidence indicated that a subpopulation of human oligodendrocytes may have dorsal origin, from cortical radial glia cells, in addition to their ventral telencephalic origin. Furthermore, we demonstrated that the regulation of myelination in the human fetal brain includes positive and negative regulators. Chemokines, such as CXCL1, abundant in proliferative zones during brain development and in regions of remyelination in adult, are discussed in the view of their potential roles in stimulating oligodendrocyte development. Other signals are inhibitory and may include, but are not limited to, polysialic acid modification of the neural cell adhesion molecule on axons. Overall, important differences in temporal and spatial distribution and regulatory signals for oligodendrocyte differentiation exist between human and rodent brains. Those differences may underlie the unique susceptibility of humans to demyelinating diseases, such as MS

The complexity of the calretinin-expressing progenitors in the human cerebral cortex

The complex structure and function of the cerebral cortex critically depend on the balance of excitation and inhibition provided by the pyramidal projection neurons and GABAergic interneurons, respectively.The calretinin-expressing (CalR+) cell is a subtype of GABAergic cortical interneurons that is more prevalent in humans than in rodents. In rodents, CalR+ interneurons originate in the caudal ganglionic eminence (CGE) from Gsx2+ progenitors, but in humans it has been suggested that a subpopulation of CalR+ cells can also be generated in the cortical ventricular/subventricular zone (VZ/SVZ). The progenitors for cortically generated CalR+ subpopulation in primates are not yet characterized. Hence, the aim of this study was to identify patterns of expression of the transcription factors (TFs) that commit cortical stem cells to the CalR fate, with a focus on Gsx2. First, we studied the expression of Gsx2 and its downstream effectors, Ascl1 and Sp8 in the cortical regions of the fetal human forebrain at midgestation. Next, we established that a subpopulation of cells expressing these TFs are proliferating in the cortical SVZ, and can be co-labeled with CalR. The presence and proliferation of Gsx2+ cells, not only in the ventral telencephalon (GE) as previously reported, but also in the cerebral cortex suggests cortical origin of a subpopulation of CalR+ neurons in humans. In vitro treatment of human cortical progenitors with Sonic hedgehog (Shh), an important morphogen in the specification of interneurons, decreased levels of Ascl1 and Sp8 proteins, but did not affect Gsx2 levels. Taken together, our ex-vivo and in vitro results on human fetal brain suggest complex endogenous and exogenous regulation of TFs implied in the specification of different subtypes of CalR+ cortical interneurons

Diversity of Cortical Interneurons in Primates: The Role of the Dorsal Proliferative Niche

Summary Evolutionary elaboration of tissues starts with changes in the genome and location of the stem cells. For example, GABAergic interneurons of the mammalian neocortex are generated in the ventral telencephalon and migrate tangentially to the neocortex, in contrast to the projection neurons originating in the ventricular/subventricular zone (VZ/SVZ) of the dorsal telencephalon. In human and nonhuman primates, evidence suggests that an additional subset of neocortical GABAergic interneurons is generated in the cortical VZ and a proliferative niche, the outer SVZ. The origin, magnitude, and significance of this species-specific difference are not known. We use a battery of assays applicable to the human, monkey, and mouse organotypic cultures and supravital tissue to identify neuronal progenitors in the cortical VZ/SVZ niche that produce a subset of GABAergic interneurons. Our findings suggest that these progenitors constitute an evolutionary novelty contributing to the elaboration of higher cognitive functions in primates