Synthesis, characterization, and cytotoxicity studies of N-(4-methoxybenzyl) thiosemicarbazone derivatives and their ruthenium(II)-p-cymene complexes

The reaction of [Ru2Cl2(μ-Cl)2(η6-p-cymene)2] with two thiosemicarbazones obtained by the condensation of N-(4-methoxybenzyl) thiosemicarbazide and 1,4-hydroxy-3-methoxyphenyl)ethan-1-one (HL1) or 2-fluoro-4-hydroxybenzaldehyde (HL2) was studied. The cationic complexes of formula [RuCl(η6-p-cymene)(HL)]+ were isolated as solid chloride and trifluoromethylsulfate (TfO) salts. A study of the solid state and NMR spectra suggests the presence in the material of two isomers that differ in the configuration in the iminic bond, C2=N3, of the coordinated thiosemicarbazone in the triflate salts and only the E isomer in the chloride. An X-ray study of single crystals of the complexes supports this hypothesis. The thiosemicarbazone ligand coordinates with the ruthenium center through the iminic and sulfur atoms to form a five-membered chelate ring. Furthermore, the isolation of single crystals containing the thiosemicarbazonate complex [Ru2(μ-L2)2(η6-p-cymene)2]2+ suggests the easy labilization of the coordinated chloride in the complex. The redox behavior of the ligands and complexes was evaluated by cyclic voltammetry. It seems to be more difficult to oxidize the complex derived from HL1 than HL2. The ability of the complexes to inhibit cell growth against the NCI-H460, A549 and MDA-MB-231 lines was evaluated. The complexes did not show greater potency than cisplatin, although they did have greater efficacy, especially for the complex derived from HL1.Ministerio de Ciencia e Innovación | Ref. PID2019-110218RB-I0

Adult entero-enteric intussusception caused by small bowel submucosal lipoma

Introduction: Intussusception is the prolapse of one gastrointestinal segment into an adjacent part. Its incidence in adults is less than 10%. Objective: To presents a case of adult entero-enteric intussusception caused by small bowel submucosal lipoma. Clinical case: A 66-year-old male patient with vague clinical manifestation that presented in a computed tomography scan typical invagination image, it showed the classical "target" and "sausage-like" images. He underwent surgery, where the diagnosis of adult entero-enteric intussusception was confirmed and then an en-bloc resection was performed. Anatomopathological examination revealed a submucosal lipoma of the jejunum. Gastrointestinal lipomas have an incidence of 0.035% - 4.4%. Conclusion: This is a rare case, not only because the intussusception is uncommon in adults but for the lead point found in it

Comparison of zebrafish and mice knockouts for Megalencephalic Leukoencephalopathy proteins indicates that GlialCAM/MLC1 forms a functional unit

Background: Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) is a rare type of leukodystrophy characterized by astrocyte and myelin vacuolization, epilepsy and early-onset macrocephaly. MLC is caused by mutations in MLC1 or GLIALCAM, coding for two membrane proteins with an unknown function that form a complex specifically expressed in astrocytes at cell-cell junctions. Recent studies in Mlc1-/- or Glialcam-/- mice and mlc1-/- zebrafish have shown that MLC1 regulates glial surface levels of GlialCAM in vivo and that GlialCAM is also required for MLC1 expression and localization at cell-cell junctions. Methods: we have generated and analysed glialcama-/- zebrafish. We also generated zebrafish glialcama-/- mlc1-/- and mice double KO for both genes and performed magnetic resonance imaging, histological studies and biochemical analyses. Results: glialcama-/- shows megalencephaly and increased fluid accumulation. In both zebrafish and mice, this phenotype is not aggravated by additional elimination of mlc1. Unlike mice, mlc1 protein expression and localization are unaltered in glialcama-/- zebrafish, possibly because there is an up-regulation of mlc1 mRNA. In line with these results, MLC1 overexpressed in Glialcam-/- mouse primary astrocytes is located at cell-cell junctions. Conclusions: this work indicates that the two proteins involved in the pathogenesis of MLC, GlialCAM and MLC1, form a functional unit, and thus, that loss-of-function mutations in these genes cause leukodystrophy through a common pathway

Megalencephalic leukoencephalopathy with subcortical cysts protein 1 regulates glial surface localization of GLIALCAM from fish to humans

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a leukodystrophy characterized by myelin vacuolization and caused by mutations in MLC1 or GLIALCAM. Patients with recessive mutations in either MLC1 or GLIALCAM show the same clinical phenotype. It has been shown that GLIALCAM is necessary for the correct targeting of MLC1 to the membrane at cell junctions, but its own localization was independent of MLC1 in vitro. However, recent studies in Mlc1−/− mice have shown that GlialCAM is mislocalized in glial cells. In order to investigate whether the relationship between Mlc1 and GlialCAM is species-specific, we first identified MLC-related genes in zebrafish and generated an mlc1−/− zebrafish. We have characterized mlc1−/− zebrafish both functionally and histologically and compared the phenotype with that of the Mlc1−/− mice. In mlc1−/− zebrafish, as in Mlc1−/− mice, Glialcam is mislocalized. Re-examination of a brain biopsy from an MLC patient indicates that GLIALCAM is also mislocalized in Bergmann glia in the cerebellum. In vitro, impaired localization of GlialCAM was observed in astrocyte cultures from Mlc1−/− mouse only in the presence of elevated potassium levels, which mimics neuronal activity. In summary, here we demonstrate an evolutionary conserved role for MLC1 in regulating glial surface levels of GLIALCAM, and this interrelationship explains why patients with mutations in either gene (MLC1 or GLIALCAM) share the same clinical phenotyp

Spread of a SARS-CoV-2 variant through Europe in the summer of 2020

[EN] Following its emergence in late 2019, the spread of SARS-CoV-21,2 has been tracked by phylogenetic analysis of viral genome sequences in unprecedented detail3,4,5. Although the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced. However, travel within Europe resumed in the summer of 2020. Here we report on a SARS-CoV-2 variant, 20E (EU1), that was identified in Spain in early summer 2020 and subsequently spread across Europe. We find no evidence that this variant has increased transmissibility, but instead demonstrate how rising incidence in Spain, resumption of travel, and lack of effective screening and containment may explain the variant’s success. Despite travel restrictions, we estimate that 20E (EU1) was introduced hundreds of times to European countries by summertime travellers, which is likely to have undermined local efforts to minimize infection with SARS-CoV-2. Our results illustrate how a variant can rapidly become dominant even in the absence of a substantial transmission advantage in favourable epidemiological settings. Genomic surveillance is critical for understanding how travel can affect transmission of SARS-CoV-2, and thus for informing future containment strategies as travel resumes.S

Docencia en Derecho y Proceso: hacia un aprendizaje de calidad en la Universidad

Presentación / Esther Pillado González (pp. 11-13). -- La adaptación de la asignatura derecho procesal penal al grado en la Universidad Carlos III de Madrid: un proceso aún inconcluso / Juan Manuel Alcoceba Gil (pp. 17-26). -- Role playing, cooperación competitiva y method case en la docencia-aprendizaje del Derecho Procesal / Cristina Alonso Salgado (pp. 27-35). -- Esquemas y materiales básicos para explicar en el grado en derecho el sistema de impugnación de actos jurídicos de las administraciones públicas en España / Roberto O. Bustillo Bolado (pp. 37-40). -- Nuevas herramientas y técnicas para la docencia del derecho / Juan Cámara Ruiz (pp. 41-51). -- Novas técnicas na docência em direito / Marco Carvalho Gonçalves (pp. 53-60). -- Experiência de lecionação em Direito em cursos não jurídicos – a lecionação da UC de Direito das Crianças e Jovens ao Mestrado em Intervenção Psicossocial com Crianças, Jovens e Famílias do Instituto de Educação / Cristina M. A. Dias (pp. 61-67). -- Los programas universitarios para mayores: la docencia en Derecho en la Universidad de Vigo / Teresa Estévez Abeleira (pp. 69-79). -- El aprendizaje activo del Derecho Procesal / María Dolores Fernández Fustes (81-92). -- El aprendizaje como método de adquirir los conocimientos / Raquel López Jiménez (pp. 93-101). -- Alumnado con necesidades especiales en el grado en derecho: el reto de la normalización e inclusión / Ángel M. Mariño de Andrés y M. Teresa Martínez Táboas (pp. 103-110). -- Docencia y proceso penal: intentando experimentar el proceso / Sabela Oubiña Barbolla (pp. 111-127). -- La integración de las redes sociales en la enseñanza del Derecho Penal / Natalia Pérez Rivas (pp. 129-135). -- Análisis y prospectiva de una plataforma e-learning en ciencias jurídicas / Amparo Rodríguez Damián, Margarita Pino Juste, Arturo Casar Sarasola y Manuel Pérez Cota (pp. 137-149). -- La evaluación de competencias en las materias “prácticas externas” del Máster Universitario en Abogacía: problemas y retos / Mónica Siota Álvarez (pp. 151-164). -- La enseñanza del derecho procesal a través del método del caso / Helena Soleto Muñoz (pp. 165-178). -- A aprendizagem activa do Direito Processual – reflexão sobre velhos hábitos e novas práticas / Lurdes Varregoso Mesquita (pp. 179-189). -- Acão executiva e metodologia aplicada – demonstração de caso / Lurdes Varregoso Mesquita, Diana Leiras (pp. 191-201). -- Derecho Constitucional y género / Almudena Bergareche Gros (pp. 205-216). -- Aproximación al fenómeno de la violencia de género a través de las novelas como recurso didáctico / María Castro Corredoira (pp. 217-227). -- La formación en género en derecho penal: el cine como recurso didáctico / Natalia Pérez Rivas, Fernando Vázquez-Portomeñe Seijas (pp. 229-240). -- Cuestiones controvertidas de la docencia en el ámbito del derecho constitucional: la perspectiva de género y el principio de transversalidad / Pablo Riquelme Vázquez (pp. 241-253). -- Storytelling y cine extranjero en la explicación del sistema de justicia penal español / Cristina Alonso Salgado (pp. 257-263). -- Direito e Cinema. Breve reflexão a partir da experiência da docência ao 1.º ano do curso de Direito / Maria Clara Calheiros (pp. 265-273). -- El cine como opción pedagógica en la enseñanza del derecho penal / Fernando Vázquez-Portomeñe Seijas y María Castro Corredoira (pp. 275-286). -- El jurista del siglo XXI y la Universidad del siglo pasado: ¿realidades irreconciliables? / Amaya Arnáiz Serrano (pp. 289-307). -- La formación del abogado del siglo XXI / Emiliano Carretero Morales (pp. 309-321). -- El cambio del perfil del alumno y su influencia a la enseñanza superior / Anna Fiodorova (pp. 323-335). -- La enseñanza del derecho en el marco Bolonia: reflexiones en base a las distintas tradiciones jurídicas / Mercedes Llorente Sánchez-Arjona (pp. 337-355)

Proceso asistencial integrado de esclerosis lateral amiotrófica

O proceso asistencial integrado da esclerose lateral amiotrófica, elaborouse co obxectivo de crear un proceso de traballo común en todas as áreas para facilitar a asistencia sanitaria ás persoas diagnosticadas desta enfermidade. Establécense actuacións como o asesoramento continuo, as consultas en acto único, a coordinación asistencial, tanto entre especialidades como coa atención primaria e a coordinación administrativa do sistema socio sanitario. Neste proceso participaron profesionais das diferentes áreas sanitarias especialistas en neuroloxía, endocrinoloxía, neumoloxía, psicoloxía clínica, rehabilitación, traballo social e hospitalización a domicilioEl proceso asistencial integrado de la esclerosis lateral amiotrófica, se elaboró con el objetivo de crear un proceso de trabajo común en todas las áreas para facilitar la asistencia sanitaria a las personas diagnosticadas de esta enfermedad. Se establecen actuaciones como el asesoramiento continuo, las consultas en acto único, la coordinación asistencial, tanto entre especialidades como con la atención primaria y la coordinación administrativa del sistema socio sanitario. En este proceso participaron profesionales de las diferentes áreas sanitarias especialistas en neurología, endocrinología, neumología, psicología clínica, rehabilitación, trabajo social y hospitalización a domicili

Buccal dental microtexture and dietary shifts in African plio-pleistocene hominins

During the middle Pliocene and early Pleistocene, the diversity of local East African ecosystems changed gradually as a response to variable climatic conditions. In this scenario, early hominins had to deal with ecological selective pressures that influenced the evolution of hominin morphology. Gracile and robust australopithecines showed an adaptative shift from diets dominated by soft C3 fruits to more abrasive, brittle, and tough resources. On the other hand, early members of our genus showed smaller teeth, thinner dental enamel and greater occlusal relief than did their Australopithecus ancestors or contemporaries Paranthropus. However, craniodental morphology and dentalmicrowear have challenged the dietary ecology interpretations. Diet reconstruction through scanning-based buccal dentalmicrowear has demonstrated a valuable tool for analyzing the highly diversfied primates diets and interpreting the hominin microwear signal. Now, it is time to move forward using 3D microtexture analysis and exploring their methodological potential. In the present study, for the first time, we have analyzed the buccal microtexture patterns in a large sample of East and South Africa Plio-Pleistocene hominins to test the potential of 37 roughness parameters (ISO/FDIS 25178) to discriminate dietary signals. Microtexture parameters were measured as the median of four independent observations of buccal surface and a stepwise Linear Discriminant Analysis (LDA) of roughness parameters showed that Sal, Sda and Vm parameters significant discriminate between Australopithecus-P.aethiopicus and H. habilis-H. ergaster, suggesting a shift in the microtexture signal between australopithecines and early Homo. Otherwise, the South African P. robustus showed more buccal-microtexture variance than east African australopithecines, suggesting the incorporation of a wide variety of hard items in their diet. Our findings demonstrate the potential of buccal microtexture to discriminate the ecological niches that hominin occupy during the Plio-Pleistocene transition and emphasize the different pattern of H. ergaster that probably had a different foraging strategy

Synthesis, Characterization, and Cytotoxicity Studies of N-(4-Methoxybenzyl) Thiosemicarbazone Derivatives and Their Ruthenium(II)-p-cymene Complexes

The reaction of [Ru2Cl2(μ-Cl)2(η6-p-cymene)2] with two thiosemicarbazones obtained by the condensation of N-(4-methoxybenzyl) thiosemicarbazide and 1,4-hydroxy-3-methoxyphenyl)ethan-1-one (HL1) or 2-fluoro-4-hydroxybenzaldehyde (HL2) was studied. The cationic complexes of formula [RuCl(η6-p-cymene)(HL)]+ were isolated as solid chloride and trifluoromethylsulfate (TfO) salts. A study of the solid state and NMR spectra suggests the presence in the material of two isomers that differ in the configuration in the iminic bond, C2=N3, of the coordinated thiosemicarbazone in the triflate salts and only the E isomer in the chloride. An X-ray study of single crystals of the complexes supports this hypothesis. The thiosemicarbazone ligand coordinates with the ruthenium center through the iminic and sulfur atoms to form a five-membered chelate ring. Furthermore, the isolation of single crystals containing the thiosemicarbazonate complex [Ru2(μ-L2)2(η6-p-cymene)2]2+ suggests the easy labilization of the coordinated chloride in the complex. The redox behavior of the ligands and complexes was evaluated by cyclic voltammetry. It seems to be more difficult to oxidize the complex derived from HL1 than HL2. The ability of the complexes to inhibit cell growth against the NCI-H460, A549 and MDA-MB-231 lines was evaluated. The complexes did not show greater potency than cisplatin, although they did have greater efficacy, especially for the complex derived from HL1

JAK/STAT blockade reverses the malignant phenotype of Hodgkin and Reed-Sternberg cells.

Constitutive activation of the JAK/STAT pathway is a common phenomenon in classic Hodgkin lymphoma (cHL). The clinical potential of anti-JAK/STAT therapy is being explored in early-stage clinical trials. Notwithstanding, very little information is available about the complex biological consequences of this blockade. Here, we investigated the effects of JAK/STAT pharmacological inhibition on cHL cell models using ruxolitinib, a JAK 1/2 inhibitor that induces apoptosis by concentration- and time-dependent mechanisms. An unbiased whole-transcriptome approach identified expression of the anti-GCSF receptor (CSF3R) as a potential surrogate biomarker of JAK/STAT overactivation. In addition, longitudinal gene expression analyses provided further mechanistic information about pertinent biological pathways involved, including 37 gene pathways distributed in 3 main clusters: cluster 1 was characterized by upregulation of the G2/M checkpoint and major histocompatibility complex-related clusters; 2 additional clusters (2 and 3) showed a progressive downregulation of the tumor-promoting inflammation signatures: JAK/STAT and interleukin 1 (IL-1)/IL-4/IL-13/IL-17. Together, our results confirm the therapeutic potential of JAK/STAT inhibitors in cHL, identify CSF3R as a new biomarker, and provide supporting genetic data and mechanistic understanding.The authors acknowledge the MD Anderson Biobank and the Spanish Biobank Network, supported by the ISCIII, for their invaluable help with tumor samples and TMAs. The authors also thank Javier Suela, from NIMGenetics, for his invaluable assistance with the gene expression analyses. This work was supported by the Instituto de Salud Carlos III (ISCIII) , cofunded by the European Regional Development Fund/European Social Fund (PI19/00083) , Ministerio de Economia, Industria y Competitividad (MINECO) (CIBERONC CB16/12/00291) , Direccion General de Universidade Investigacion Consejeria de Educacion e Investigacion de la Comunidad de Madrid (B2017/BMD-3778) , and a Roche Foundation Research Grant; V.M. is a recipient of an iPFIS predoctoral fellowship from ISCIII-AES-2020 (FI20/00184) .S