Post-Franco Theatre

In the multiple realms and layers that comprise the contemporary Spanish theatrical landscape, “crisis” would seem to be the word that most often lingers in the air, as though it were a common mantra, ready to roll off the tongue of so many theatre professionals with such enormous ease, and even enthusiasm, that one is prompted to wonder whether it might indeed be a miracle that the contemporary technological revolution – coupled with perpetual quandaries concerning public and private funding for the arts – had not by now brought an end to the evolution of the oldest of live arts, or, at the very least, an end to drama as we know it

Understanding the maintenance of neuromuscular integrity: role of CtBP1 and EZH2 in skeletal muscle response to denervation

Loss of functional innervation of skeletal muscles is key in several pathologies, including sarcopenia. Neuromuscular junctions (NMJs) maintenance involves local expression of synaptic genes restricted to sub-synaptic nuclei, and a proper response to spontaneous denervation to re-innervate and preserve muscle functions. We hypothesized that the Akt/mTORC1 signaling pathway acts as a regulatory platform coordinating muscle responses to denervation. During my PhD, I characterized the expression pattern of two candidate targets, C-terminal binding protein 1 (CtBP1) and enhancer of zeste homolog 2 (EZH2) in both innervated and denervated conditions. I also studied the consequences of knocking down and/or overexpressing CtBP1 or EZH2 on synaptic gene expression, NMJ maintenance, muscle histology and metabolism. Lastly, I evaluated the role of Akt/mTORC1 in the regulation of CtBP1 and EZH2 in skeletal muscle, by comparing their expression pattern in control and TSCmKO mice, characterized by Akt/mTORC1 deregulation and used as a model for sarcopenia

Genome-Wide DNA from Degraded Petrous Bones and the Assessment of Sex and Probable Geographic Origins of Forensic Cases

The acquisition of biological information and assessment of the most probable geographic origin of unidentified individuals for obtaining positive identification is central in forensic sciences. Identification based on forensic DNA, however, varies greatly in relation to degradation of DNA. Our primary aim is to assess the applicability of a petrous bone sampling method in combination with Next Generation Sequencing to evaluate the quality and quantity of DNA in taphonomically degraded petrous bones from forensic and cemetery cases. A related aim is to analyse the genomic data to obtain the molecular sex of each individual, and their most probable geographic origin. Six of seven subjects were previously identified and used for comparison with the results. To analyse their probable geographic origin, samples were genotyped for the 627.719 SNP positions. Results show that the inner ear cochlear region of the petrous bone provides good percentages of endogenous DNA (14.61\u201366.89%), even in the case of burnt bodies. All comparisons between forensic records and genetic results agree (sex) and are compatible (geographic origin). The application of the proposed methodology may be a powerful tool for use in forensic scenarios, ranging from missing persons to unidentified migrants who perish when crossing borders

New mutation in the beta 1 propeller domain of LRP4 responsible for congenital myasthenic syndrome associated with Cenani-Lenz syndrome

International audienceCongenital myasthenic syndromes are a clinically and genetically heterogeneous group of inherited disorders caused by defective synaptic transmission at the neuromuscular junction, characterized by muscle weakness and fatigability. Until now, many mutations encoding postsynaptic proteins as Agrin, MuSK and LRP4 have been identified as responsible for increasingly complex CMS phenotypes. The majority of mutations identified in LRP4 gene causes bone diseases including CLS and sclerosteosis-2 and in rare cases of CMS with mutations in LRP4 gene has been described so far.In the French cohort of CMS patients, we identified a novel LRP4 homozygous missense mutation (c.1820A>G; p.Thy607Cys) within the 1 propeller domain in a patient presenting CMS symptoms, including muscle weakness, fluctuating fatigability and a decrement in compound muscle action potential (CMAP) in spinal nerves, associated with congenital agenesis of the hands and feet and renal malformation. Expression studies revealed the decrease of agrin and Wnt11 binding to mutated β1 propeller domain leading to a disruption of LRP4/MuSK signaling associated with a lack of AChR aggregation in patient myotubes. Little improvement in the patient's symptoms were observed with the treatments usually used for CMS.To date, mutations in the LRP4 gene have been reported in several different phenotypes including CLS and CMS but never associated together in the same patient. Besides, this study appears useful for the future diagnosis and treatment of patients with co-existing CLS and CMS and highlights the importance of structural and functional studies in the diagnosis and possible treatment of these atypical forms

Identification of a muscle-specific isoform of VMA21 as a potent actor in X-linked myopathy with excessive autophagy pathogenesis

Defective lysosomal acidification is responsible for a large range of multi-systemic disorders associated with impaired autophagy. Diseases caused by mutations in the VMA21 gene stand as exceptions, specifically affecting skeletal muscle (X-linked Myopathy with Excessive Autophagy, XMEA) or liver (Congenital Disorder of Glycosylation). VMA21 chaperones vacuolar (v-) ATPase assembly, which is ubiquitously required for proper lysosomal acidification. The reason VMA21 deficiencies affect specific, but divergent tissues remains unknown. Here, we show that VMA21 encodes a yet-unreported long protein isoform, in addition to the previously described short isoform, which we name VMA21-120 and VMA21-101, respectively. In contrast to the ubiquitous pattern of VMA21-101, VMA21-120 was predominantly expressed in skeletal muscle, and rapidly up-regulated upon differentiation of mouse and human muscle precursors. Accordingly, VMA21-120 accumulated during development, regeneration and denervation of mouse skeletal muscle. In contrast, neither induction nor blockade of autophagy, in vitro and in vivo, strongly affected VMA21 isoform expression. Interestingly, VMA21-101 and VMA21-120 both localized to the sarcoplasmic reticulum of muscle cells, and interacted with the v-ATPase. While VMA21 deficiency impairs autophagy, VMA21-101 or VMA21-120 overexpression had limited impact on autophagic flux in muscle cells. Importantly, XMEA-associated mutations lead to both VMA21-101 deficiency and loss of VMA21-120 expression. These results provide important insights into the clinical diversity of VMA21-related diseases and uncover a muscle-specific VMA21 isoform that potently contributes to XMEA pathogenesis

New mutation in the β1 propeller domain of LRP4 responsible for congenital myasthenic syndrome associated with Cenani–Lenz syndrome

International audienceCongenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of rare diseases due to mutations in neuromuscular junction (NMJ) protein-coding genes. Until now, many mutations encoding postsynaptic proteins as Agrin, MuSK and LRP4 have been identified as responsible for increasingly complex CMS phenotypes. The majority of mutations identified in LRP4 gene causes bone diseases including CLS and sclerosteosis-2 and rare cases of CMS with mutations in LRP4 gene has been described so far. In the French cohort of CMS patients, we identified a novel LRP4 homozygous missense mutation (c.1820A > G; p.Thy607Cys) within the β1 propeller domain in a patient presenting CMS symptoms, including muscle weakness, fluctuating fatigability and a decrement in compound muscle action potential in spinal accessory nerves, associated with congenital agenesis of the hands and feet and renal malformation. Mechanistic expression studies show a significant decrease of AChR aggregation in cultured patient myotubes, as well as altered in vitro binding of agrin and Wnt11 ligands to the mutated β1 propeller domain of LRP4 explaining the dual phenotype characterized clinically and electoneuromyographically in the patient. These results expand the LRP4 mutations spectrum associated with a previously undescribed clinical association involving impaired neuromuscular transmission and limb deformities and highlighting the critical role of a yet poorly described domain of LRP4 at the NMJ. This study raises the question of the frequency of this rare neuromuscular form and the future diagnosis and management of these cases

Benito Pérez Galdós

In Galdós\u27 time, the tensions between such diverse phenomena as coins and credit, free trade and protectionist tariffs, factory work and domestic economy, masculine and feminine, and private and public exacerbated friction among peoples—those of pueblo and rural origins, whose voices rasped and whose bright colors raked the eye, and a nascent, insecure bourgeosie who, fearful of the masses, strove to imitate the aristocracy. Old and new converged also with the question of suffrage and citizenship to aggravate social malaise and political upheavals—Carlist wars, palace intrigues, the Revolution of 1868 and overthrow of Queen Isabel, the brief reign of Amadeo of Savoy, the aborted First Republic and the Bourbon Restoration (1875-1885), which reached Spain from England in the imported person of Alfonso XII. These turbulent events undergird the cultural, historical, and political events of the novels by Benito Pérez Galdós (1843–1920) to be discussed in this chapter. Galdós is the author of seventy-seven novels, twenty-six original plays, and numerous occasional pieces, written between 1867 and 1920. These divide into two main categories: the historical and the contemporary social novels, now more appropriately described as novels of modernity The forty-six historical novels, called Episodios nacionales, make up five series, each consisting of ten interconnected novels, except the fifth series, left unfinished. The thirty-one novels of modernity, published between 1870 and 1915, also divide into two groups: Novelas de la primera época ( Novels of the Early Period, 1870–1879) and Las novelas de la serie contemporánea ( The Contemporary Social Novels, 1881–1915). The novels of the early period comprise Galdós\u27 first attempts at novel writing, as well as four so-called thesis novels : Doña Perfecta (1876), the sequel Gloria (1876–1877), Marianela (1878), and La familia de León Roch ( The Family of León Roch, 1878–1879). The next group of novels represents what Galdós called his segunda manera —his second style, a different kind of writing ... a more sophisticated and varied mode of narrative presentation