Desenvolupament d'una aplicació educativa per al disseny de turbines des del punt de vista Termodinàmic

This final degree project is a programming project whose objective is to create a website to develop an interactive application that illustrates the thermodynamic processes and cycles that occur in an airplane turbine. The application also has a couple of turbojet and turbofan exercises, where the user must set working conditions and other parameters, according to design requirements, in the future this part will be expanded. Within the website there is also a part of thermodynamics theory and ideal gas exercises. The purpose of the website is to help students and teachers better understand thermodynamics and facilitate the time of doing exercises and theory. The report initially explained what programming language I used and why, there was also a comparison between the Matlab language and Python, since they were the two languages I could use, finally I decided that the best option was to use Python. Once explained the programming language explains how I started programming the exercises of cycles and thermodynamic processes that I wanted to include on the website using PyCharm, to do this initially I had to decide how I wanted to do the exercises and what information I wanted the user to give me, at this point it also explains how I created the graphics. The next point talks about the tools needed to carry out the website, it explains what the Visual Studio Code is and how it works, this program is the one I used to carry out the website, it also explains the extensions I used and the HTML. And to finish chapter 1 explains the internal structure of the website, the website consists of a file called app.py that is responsible for connecting the different files and then a folder of templates consisting of six more folders where the HTML files for each language are. The next chapter explains the result of the website, the first point of chapter two explains its design and operation, that is, the different sections it has and how to move from one place to another, it also explains how the exercises work. And the next and last point of chapter 2, explains how to publish the website, initially I just wanted to share the website with my tutors, so, to do this I used a program called Ngrok, and then I used a hosting to be able to publish the website and make it accessible to any user. Finally, there are the conclusions. To finish this summary, it must be said that I have achieved the objective of the project that was to create a website of educational thermodynamics

Estudio de las miopatias distales, en particular de una forma endemica de la región de la Safor

Las miopatías distales son un grupo heterogéneo de enfermedades musculares hereditarias, relativamente prevalentes en la Comunidad Valenciana, España. En este trabajo se han estudiado pacientes con una miopatía distal anterior de herencia autosómico dominante pertenecientes a siete familias, cuatro de las cuales proceden de la comarca de La Safor. Se elaboraron los pedigríes y se evaluó clínicamente a los pacientes. Con posterioridad se valoró la posible asociación de neuropatía y/o miocardiopatía y se estudió el patrón de afectación muscular mediante pruebas de imagen, los hallazgos neurofisiológicos, y los rasgos miopatológicos. Se realizó un abordaje genético de los pacientes, mediante secuenciación y haplotipos. Los pacientes de las diferentes familias estudiadas presentaron un fenotipo clínico similar, para el mismo grado de gravedad de la enfermedad, pero se constató una ostensible variabilidad interindividual, intrafamiliar e interfamiliar. Aunque la afectación de la musculatura anterior de la pierna fue el rasgo común en todos ellos, algunos pacientes manifestaron un fenotipo escápulo-peroneal o de cinturas. Mediante técnicas de imagen muscular se corroboró la frecuente implicación de musculatura proximal y axial, y se definió un patrón de afectación muscular característico. Aunque se descartó la asociación con neuropatía, en los estudios neurofisiológicos frecuentemente aparecieron rasgos neurógenos, que pueden ser secundarios a fenómenos de remodelación de la unidad motora. Sólo un paciente asoció miocardiopatía, indicando que la afectación del miocardio es posible pero infrecuente. Los hallazgos patológicos más consistentes fueron el predominio/hipotrofia de las fibras tipo 1; las alteraciones en la actividad enzimática oxidativa constituyendo cores/multi-minicores; y las anomalías mitocondriales. Todos los pacientes pertenecientes a las familias de La Safor segregaron la mutación p.K1729del en MYH7 conocida por producir la miopatía de Laing. Los estudios de haplotipos indicaron que dicha mutación es fundadora y tiene un origen ancestral común con la familia Italo-Americana descrita por Hedera y col. En las familias restantes un ligamiento con MYH7 es posible, aunque todavía no se ha identificado la mutación causal.Distal myopathies are a heterogeneous group of inherited muscle disorders, relatively prevalent in the Comunidad Valenciana, Spain. This thesis is the study of patients with a dominant inherited distal anterior myopathy, from seven families, four of them originating from La Safor region. Initially, the pedigrees were prepared and patients were clinically evaluated. The association with neuropathy and/or cardiomyopathy was considered. To further characterized the disease, muscle imaging, neurophysiological and muscle biopsy studies were performed. Genetic assessment included sequencing and haplotyping studies. Patients from different families harboured a similar phenotype, depending on the degree of severity of the disease, though a large interindividual variability, intrafamilial and interfamilial, was evident. Although the involvement of the anterior compartment of the lower leg was the hallmark of the disease, some patients harboured different clinical phenotypes including limb-girdle or scapulo-peroneal syndromes. A homogeneous pattern of muscle involvement and the frequent involvement of limb girdle and axial muscles were corroborated by muscle imaging techniques. The association with neuropathy was ruled out although neurogenic features, probably related to an abnormal motor unit remodelation process, were found. The presence of cardiomyopathy only in one patient made this association possible but rare. Fibre type 1 predominance and hypotrophy, irregular enzyme activity with core/multi-minicore structures and mitochondrial abnormalities were the most consistent pathological findings. All patients from La Safor segregated the p.K1729del mutation in MYH7, known to cause Laing myopathy. Haplotype studies indicate that p.K1729del mutation in La Safor patients indeed is a common founder mutation. A common ancestral origin with the Italian-American family reported by Hedera et al is suggested. In patients from outside La Safor, the haplotypes showed a possible linkage of the myopathy with MYH7 gene, although any mutation has still not been identified

Evolutionary conserved role of eukaryotic translation factor eIF5A in the regulation of actin-nucleating formins

Elongation factor eIF5A is required for the translation of consecutive prolines, and was shown in yeast to translate polyproline-containing Bni1, an actin-nucleating formin required for polarized growth during mating. Here we show that Drosophila eIF5A can functionally replace yeast eIF5A and is required for actin-rich cable assembly during embryonic dorsal closure (DC). Furthermore, Diaphanous, the formin involved in actin dynamics during DC, is regulated by and mediates eIF5A effects. Finally, eIF5A controls cell migration and regulates Diaphanous levels also in mammalian cells. Our results uncover an evolutionary conserved role of eIF5A regulating cytoskeleton-dependent processes through translation of formins in eukaryotes

Vocal cord paresis and diaphragmatic dysfunction are severe and frequent symptoms of GDAP1-associated neuropathy

[EN] Cranial nerve involvement in Charcot-Marie-Tooth disease (CMT) is rare, though there are a number of CMT syndromes in which vocal cord paralysis is a characteristic feature. CMT disease due to mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) has been reported to be associated with vocal cord and diaphragmatic palsy. In order to address the prevalence of these complications in patients with GDAP1 mutations we evaluated vocal cord and respiratory function in nine patients from eight unrelated families with this disorder. Hoarseness of the voice and inability to speak loudly were reported by eight patients and one had associated symptoms of respiratory insufficiency. Patients were investigated by means of peripheral and phrenic nerve conduction studies, flexible laryngoscopy, pulmonary function studies and polysomnography. Nerve conduction velocities and pathological studies were compatible with axonal CMT (CMT2). Flexible laryngoscopy showed left vocal cord palsy in four cases, bilateral cord palsies in four cases and was normal in one case. Restrictive respiratory dysfunction was seen in the eight patients with vocal cord paresis who were all chair-bound. These eight had confirmed phrenic nerve dysfunction on neurophysiology evaluation. The patient with normal vocal cord and pulmonary function had a less severe clinical course.This study shows that CMT patients with GDAP1 mutations develop severe disability due to weakness of limb muscles and that laryngeal and respiratory muscle involvement occurs late in the disease process when significant proximal upper limb weakness has developed. The early and predominant involvement of the left vocal cord innervated by the longer left recurrent laryngeal nerve suggests a length dependent pattern of nerve degeneration. In GDAP1 neuropathy, respiratory function should be thoroughly investigated because life expectancy can be compromised due to respiratory failure.Fondo de Investigacion Sanitaria (PI/05/1572); CIBERNED; CIBERER; Instituto de Salud Carlos III.Sevilla, T.; Jaijo, T.; Nauffal, D.; Collado, D.; Chumillas, MJ.; Vilchez, JJ.; Muelas, N.... (2008). Vocal cord paresis and diaphragmatic dysfunction are severe and frequent symptoms of GDAP1-associated neuropathy. Brain. 131:3051-3061. https://doi.org/10.1093/brain/awn2283051306113

Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease

[EN] Mutations in the ganglioside-induced-differentiation-associated protein 1 gene (GDAP1) can cause Charcot-Marie-Tooth (CMT) disease with demyelinating (CMT4A) or axonal forms (CMT2K and ARCMT2K). Most of these mutations present a recessive inheritance, but few autosomal dominant GDAP1 mutations have also been reported. We performed a GDAP1 gene screening in a clinically well-characterized series of 81 index cases with axonal CMT neuropathy, identifying 17 patients belonging to 4 unrelated families in whom the heterozygous p.R120W was found to be the only disease-causing mutation. The main objective was to fully characterize the neuropathy caused by this mutation. The clinical picture included a mild-moderate phenotype with onset around adolescence, but great variability. Consistently, ankle dorsiflexion and plantar flexion were impaired to a similar degree. Nerve conduction studies revealed an axonal neuropathy. Muscle magnetic resonance imaging studies demonstrated selective involvement of intrinsic foot muscles in all patients and a uniform pattern of fatty infiltration in the calf, with distal and superficial posterior predominance. Pathological abnormalities included depletion of myelinated fibers, regenerative clusters and features of axonal degeneration with mitochondrial aggregates. Our findings highlight the relevance of dominantly transmitted p.R120W GDAP1 gene mutations which can cause an axonal CMT with a wide clinical profile.We are grateful to the propositi and their relatives for their kind collaboration. We also want to thank I. Llopis and M. Escutia for their help with sample management. This work was supported by the Instituto de Salud Carlos III [PI08/90857, PI08/0889, CP08/00053 and PS09/00095], the Fundacion para la Investigacion del Hospital Universitari La Fe [CM06/00154], the Spanish Ministry Science and Innovation [grant number SAF2006-01047], and the Generalitat Valenciana [grant no. Prometeo/2009/05]. Dr. C. Espinos has a "Miguel Servet'' contract funded by the Fondo de Investigacion Sanitaria. Both Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER) and Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED) are initiatives from the Instituto de Salud Carlos III.Sivera, R.; Espinós-Armero, CÁ.; Vílchez, JJ.; Mas, F.; Martínez-Rubio, D.; Chumillas, MJ.; Mayordomo, F.... (2010). Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease. Journal of the Peripheral Nervous System. 15(4):334-344. https://doi.org/10.1111/j.1529-8027.2010.00286.x33434415

Transcriptomic Evidence of the Immune Response Activation in Individuals With Limb Girdle Muscular Dystrophy Dominant 2 (LGMDD2) Contributes to Resistance to HIV-1 Infection

LGMDD2 is a rare form of muscular dystrophy characterized by one of the three heterozygous deletions described within the TNPO3 gene that result in the addition of a 15-amino acid tail in the C-terminus.TNPO3 is involved in the nuclear import of splicing factors and acts as a host cofactor for HIV-1 infection by mechanisms not yet deciphered. Further characterization of the crosstalk between HIV-1 infection and LGMDD2 disease may contribute to a better understanding of both the cellular alterations occurring in LGMDD2 patients and the role of TNPO3 in the HIV-1 cycle. To this regard, transcriptome profiling of PBMCs from LGMDD2 patients carrying the deletion c.2771delA in the TNPO3 gene was compared to healthy controls. A total of 545 differentially expressed genes were detected between LGMDD2 patients and healthy controls, with a high representation of G protein-coupled receptor binding chemokines and metallopeptidases among the most upregulated genes in LGMDD2 patients. Plasma levels of IFN-β and IFN-γ were 4.7- and 2.7-fold higher in LGMDD2 patients, respectively. An increase of 2.3-fold in the expression of the interferon-stimulated gene MxA was observed in activated PBMCs from LGMDD2 patients after ex vivo HIV-1 pseudovirus infection. Thus, the analysis suggests a pro-inflammatory state in LGMDD2 patients also described for other muscular dystrophies, that is characterized by the alteration of IL-17 signaling pathway and the consequent increase of metallopeptidases activity and TNF response. In summary, the increase in interferons and inflammatory mediators suggests an antiviral environment and resistance to HIV-1 infection but that could also impair muscular function in LGMDD2 patients, worsening disease evolution. Biomarkers of disease progression and therapeutic strategies based on these genes and mechanisms should be further investigated for this type of muscular dystrophy.This study was funded by Asociación Conquistando Escalones, French Agency for Research on AIDS and Viral Hepatitis (ANRS grant ECTZ107263), Instituto de Salud Carlos III (PI19CIII/00004), NIH grant R01AI143567, the Spanish Ministry of Science and Innovation (PID2019-110275RB I00) and Fundación Isabel Gemio. It has been conducted within the Spanish AIDS Research Network (RIS) and Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, funded by Instituto de Salud Carlos 640 III (Plan Estatal de I+D+I 2013-2016) and co-funded by European Regional Development Fund (ERDF) “A way to build Europe” (RD16CIII/0002/0001).S

Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease

[EN] Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p. R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p. R190W mutation and another patient that harboured a MORC2 p. S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.This collaborative joint project is awarded by IRDiRC and funded by the Instituto de Salud Carlos III (ISCIII) - Subdireccion General de Evaluacion y Fomento de la Investigacion within the framework of the National R+D+I Plan (IR11/TREAT-CMT to T.S., S.I.P.P., F.P. and C.E.; PI12/00453 to C.E.; and PI12/0946 to T.S.), co-funded with FEDER funds. Additional support was provided by the Ramon Areces Foundation and by the ISCIII and the Centro de Investigacion Principe Felipe (CPII14/00002) to C.E.Sevilla, T.; Lupo, V.; Martínez-Rubio, D.; Sancho, P.; Sivera, R.; Chumillas, MJ.; García-Romero, M.... (2016). Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease. Brain. 139:62-72. https://doi.org/10.1093/brain/awv311627213

Muscle imaging in laminopathies: Synthesis study identifies meaningful muscles for follow-up

Introduction: Particular fibroadipose infiltration patterns have been recently described by muscle imaging in congenital and later onset forms of LMNA-related muscular dystrophies (LMNA-RD). Methods: Scores for fibroadipose infiltration of 23 lower limb muscles in 34 patients with LMNA-RD were collected from heat maps of 2 previous studies. Scoring systems were homogenized. Relationships between muscle infiltration and disease duration and age of onset were modeled with random forests. Results: The pattern of infiltration differs according to disease duration but not to age of disease onset. The muscles whose progression best predicts disease duration were semitendinosus, biceps femoris long head, gluteus medius, and semimembranosus. Discussion: In LMNA-RD, our synthetic analysis of lower limb muscle infiltration did not find major differences between forms with different ages of onset but allowed the identification of muscles with characteristic infiltration during disease progression. Monitoring of these specific muscles by quantitative MRI may provide useful imaging biomarkers in LMNA-RD. Muscle Nerve 58:812-817, 201

Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment

Background:Niemann-Pick disease Type C (NPC) is a genetic, incurable, neurodegenerative disorder. This orphan disease is most frequently caused by mutations in the NPC1 protein, resulting in intralysossomal cholesterol accumulation. NPC1 is found in neuronal cell bodies, axon terminals and synaptosomes, suggesting it plays a role in lysosomal degradation pathway and in synaptic transmission. Neuronal function is especially vulnerable to NPC1 deficiency and synaptic changes seem a key element in disease development. Currently, Miglustat (Zavesca (R)) is the only approved treatment for NPC. However, preclinical evidence showed that low-dose Efavirenz reverted synaptic defects through pharmacological activation of the enzyme CYP46. Methods:This is a single-center, phase II clinical trial to evaluate the efficacy and safety of Efavirenz in addition to standard of care in patients diagnosed with adult or late juvenile-onset NPC with cognitive impairment. All enrolled patients will be treated orally with 25 mg/d of Efavirenz for 52 weeks (1 year). Secondary objectives include evaluating clinical (neurological and neuropsychological questionnaires) and biological (imaging and biochemical biomarkers) parameters. Discussion:NPC is still an unmet medical need. Although different therapeutic approaches are under study, this is the first clinical trial (to the best of our knowledge) studying the effects of Efavirenz in adult- and late-juvenile-onset NPC. Despite the small sample size and the single-arm design, we expect the results to show Efavirenz's capacity of activating the CYP46 enzyme to compensate for NPC1 deficiency and correct synaptic changes, therefore compensating cognitive and psychiatric changes in these patients. This study may provide direct benefit to enrolled patients in terms of slowing down the disease progression

Dystrophinopathy Phenotypes and Modifying Factors in Exon 45-55 Deletion

Duchenne muscular dystrophy (DMD) exon 45-55 deletion (del45-55) has been postulated as a model that could treat up to 60% of DMD patients, but the associated clinical variability and complications require clarification. We aimed to understand the phenotypes and potential modifying factors of this dystrophinopathy subset. This cross-sectional, multicenter cohort study applied clinical and functional evaluation. Next generation sequencing was employed to identify intronic breakpoints and their impact on the Dp140 promotor, intronic long noncoding RNA, and regulatory splicing sequences. DMD modifiers (SPP1, LTBP4, ACTN3) and concomitant mutations were also assessed. Haplotypes were built using DMD single nucleotide polymorphisms. Dystrophin expression was evaluated via immunostaining, Western blotting, reverse transcription polymerase chain reaction (PCR), and droplet digital PCR in 9 muscle biopsies. The series comprised 57 subjects (23 index) expressing Becker phenotype (28%), isolated cardiopathy (19%), and asymptomatic features (53%). Cognitive impairment occurred in 90% of children. Patients were classified according to 10 distinct index-case breakpoints; 4 of them were recurrent due to founder events. A specific breakpoint (D5) was associated with severity, but no significant effect was appreciated due to the changes in intronic sequences. All biopsies showed dystrophin expression of >67% and traces of alternative del45-57 transcript that were not deemed pathogenically relevant. Only the LTBP4 haplotype appeared associated the presence of cardiopathy among the explored extragenic factors. We confirmed that del45-55 segregates a high proportion of benign phenotypes, severe cases, and isolated cardiac and cognitive presentations. Although some influence of the intronic breakpoint position and the LTBP4 modifier may exist, the pathomechanisms responsible for the phenotypic variability remain largely unresolved. ANN NEUROL 2022;92:793-80