The APC/C Ubiquitin Ligase: From Cell Biology to Tumorigenesis

The ubiquitin proteasome system (UPS) is required for normal cell proliferation, vertebrate development, and cancer cell transformation. The UPS consists of multiple proteins that work in concert to target a protein for degradation via the 26S proteasome. Chains of an 8.5-kDa protein called ubiquitin are attached to substrates, thus allowing recognition by the 26S proteasome. Enzymes called ubiquitin ligases or E3s mediate specific attachment to substrates. Although there are over 600 different ubiquitin ligases, the Skp1–Cullin–F-box (SCF) complexes and the anaphase promoting complex/cyclosome (APC/C) are the most studied. SCF involvement in cancer has been known for some time while APC/C’s cancer role has recently emerged. In this review we will discuss the importance of APC/C to normal cell proliferation and development, underscoring its possible contribution to transformation. We will also examine the hypothesis that modulating a specific interaction of the APC/C may be therapeutically attractive in specific cancer subtypes. Finally, given that the APC/C pathway is relatively new as a cancer target, therapeutic interventions affecting APC/C activity may be beneficial in cancers that are resistant to classical chemotherapy

Nova diana terapèutica per al tractament de les lesions medul·lars

Investigadores del grup de Neuroplasticitat i Regeneració de la UAB han descobert una teràpia farmacològica basada en la modulació de mecanismes epigenètics que regulen la neuroinflamació de les lesions medul·lars. Els resultats obtinguts en aquest estudi, realitzat en ratolins, podrien suposar un pas edavant cap a un tractament que millori la funció i la qualitat de vida dels pacients.Investigadoras del grupo de Neuroplasticidad y Regeneración de la UAB han descubierto una terapia farmacológica basada en la modulación de mecanismos epigenéticos que regulan la neuroinflamación de las lesiones medulares. Los resultados obtenidos en este estudio, realizado en ratones, podrían suponer un paso más hacia un tratamiento que mejore la función y la calidad de vida de los pacientes

Keys to improving undergraduate teaching through coordination: a research proposal

Esta investigación presenta los resultados de un proyecto de innovación docente que se propuso, al concluir el proceso de implantación de un nueva titulación de grado, analizar el modo en que el despliegue docente se adecua a la planificación inicial presentada a verificación. En la creencia de que uno de los pilares fundamentales y más desatendidos de la calidad docente es la coordinación, en el momento de abordar el proyecto nos marcamos tres objetivos: (1) analizar todas las guías docentes de cada uno de los cuatro cursos «desde el punto de vista del estudiante» prestando especial atención a (i) la carga de trabajo del estudiante a lo largo del semestre; (ii) la adecuación de los sistemas de evaluación; y (iii) los posibles solapamientos a lo largo del plan de estudios; (2) cruzar las competencias de la memoria de verificación (ligadas a materias) con las competencias de las guías docentes (ligadas a asignaturas) para evitar que hubiera competencias trabajadas en exceso o que no se abordaran en ninguna asignatura; y (3) dar a conocer entre los estudiantes la noción de «competencias» y hacer que participaran en el proceso de reflexión sobre su adquisición y evaluación. Tras el análisis llevado a cabo podemos afirmar que, de hecho, los problemas más graves tienen su origen en la falta de coordinación del profesorado, que acarrea (a) desequilibrios en la carga de trabajo del estudiante; (b) improvisación en la implantación de innovaciones docentes ligadas a la evaluación; y (c) escasa asunción de la importancia de la «competencias» tanto por parte de los estudiantes como, lo que es peor, por parte de los docentes, en tanto que provoca lagunas y solapamientos a lo largo del gradoOnce deployed in full the implementation process of a new bachelor degree tuned in with the European Higher Education Area scheme and the Bologna principles, we present the results of a project aimed at assessing the alignment of the actual degree with the proposal verified by an external quality assessment agency prior to launching the degree. Coordination is and has always been a key factor in the success of academic enterprises, but unfortunately a traditionally neglected one too. This is why we launched a project aimed at: (1) analyzing all the module handbooks in the degree “from a student stance”, focusing on (i) student workload over the semester; (ii) assessment procedures; and (iii) eventual overlaps over the four-year degree; (2) matching the skills and competences included in the degree layout as approved by the quality assessment agency (linked to broad content fields) with the skills and competences included in the actual handbooks (linked to specific courses) so as to detect and prevent neglecting or overexposing students to any of them; and (3) disseminating the notion of “skills and competences” among students, to integrate them in the reflection process about their acquisition and assessment. After our study, we can actually confirm that the most serious flaws in the degree originate in the lack of coordination among lecturers, which motivates (a) unbalances in student workload; (b) lack of planning in the adoption of teaching and assessing innovative practices; and (c) a poor understanding of the relevance of the notion of “skills and competences”, both by students and (more significantly, in that it brings along overlaps and gaps over the degree) by lecturersEsta investigación se enmarca dentro del Proyecto de Innovación coordinación docente para la mejora de la calidad de la enseñanza-aprendizaje en el grado en Lenguas Modernas, Cultura y Comunicación» (referencia FyL-L2-6 de la Convocatoria de Proyectos para el Desarrollo de las Enseñanzas 2012 de la Universidad Autónoma de Madrid), del cual fue investigadora principal (IP) Clara Molina Ávila e investigadora colaboradora (IC) Mª Azucena Penas Ibáñez, junto con otros colaboradores del equipo investigador-docent

Voluntary wheel running preserves lumbar perineuronal nets, enhances motor functions and prevents hyperreflexia after spinal cord injury

Altres ajuts: Fundació La Marató-TV3 (TV3-201736-30-31)Perineuronal nets (PNN) are a promising candidate to harness neural plasticity since their activity-dependent modulation allows to either stabilize the circuits or increase plasticity. Modulation of plasticity is the basis of rehabilitation strategies to reduce maladaptive plasticity after spinal cord injuries (SCI). Hence, it is important to understand how spinal PNN are affected after SCI and rehabilitation. Thus, this work aims to describe functional and PNN changes after thoracic SCI in mice, followed by different activity-dependent therapies: enriched environment, voluntary wheel and forced treadmill running. We found that the contusion provoked thermal hyperalgesia, hyperreflexia and locomotor impairment as measured by thermal plantar test, H wave recordings and the BMS score of locomotion, respectively. In the spinal cord, SCI reduced PNN density around lumbar motoneurons. In contrast, activity-based therapies increased motoneuron activity and reversed PNN decrease. The voluntary wheel group showed full preservation of PNN which also correlated with reduced hyperreflexia and better locomotor recovery. Furthermore, both voluntary wheel and treadmill running reduced hyperalgesia, but this finding was independent of lumbar PNN levels. In the brainstem sensory nuclei, SCI did not modify PNN whereas some activity-based therapies reduced them. The results of the present study highlight the impact of SCI on decreasing PNN at caudal segments of the spinal cord and the potential of physical activity-based therapies to reverse PNN disaggregation and to improve functional recovery. As modulating plasticity is crucial for restoring damaged neural circuits, regulating PNN by activity is an encouraging target to improve the outcome after injury

Lack of a synergistic effect of a non-viral ALS gene therapy based on BDNF and a TTC fusion molecule

Significant improvements in behavioral and electrophysiological results, motoneuron survival and anti-apoptotic/survival-activated pathways were observed with BDNF-TTC treatment. However, no synergistic effect was found for this fusion molecule. Although BDNF in the fusion molecule is capable of activating autocrine and neuroprotective pathways, TTC treatment alone yielded similar neuroprotection. Therefore, an accurate study of the neuroprotective effects of TTC fusion molecules should be performed to obtain a better understanding of its effect

BET protein inhibition regulates cytokine production and promotes neuroprotection after spinal cord injury

Spinal cord injury (SCI) usually causes a devastating lifelong disability for patients. After a traumatic lesion, disruption of the blood-spinal cord barrier induces the infiltration of macrophages into the lesion site and the activation of resident glial cells, which release cytokines and chemokines. These events result in a persistent inflammation, which has both detrimental and beneficial effects, but eventually limits functional recovery and contributes to the appearance of neuropathic pain. Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that regulate the expression of inflammatory genes by interacting with acetylated lysine residues. While BET inhibitors are a promising therapeutic strategy for cancer, little is known about their implication after SCI. Thus, the current study was aimed to investigate the anti-inflammatory role of BET inhibitors in this pathologic condition. We evaluated the effectiveness of the BET inhibitor JQ1 to modify macrophage reactivity in vitro and to modulate inflammation in a SCI mice model. We analyzed the effects of BET inhibition in pro-inflammatory and anti-inflammatory cytokine production in vitro and in vivo. We determined the effectiveness of BET inhibition in tissue sparing, inflammation, neuronal protection, and behavioral outcome after SCI. We have found that the BET inhibitor JQ1 reduced the levels of pro-inflammatory mediators and increased the expression of anti-inflammatory cytokines. A prolonged treatment with JQ1 also decreased reactivity of microglia/macrophages, enhanced neuroprotection and functional recovery, and acutely reduced neuropathic pain after SCI. BET protein inhibition is an effective treatment to regulate cytokine production and promote neuroprotection after SCI. These novel results demonstrate for the first time that targeting BET proteins is an encouraging approach for SCI repair and a potential strategy to treat other inflammatory pathologies. The online version of this article (10.1186/s12974-019-1511-7) contains supplementary material, which is available to authorized users

Immunological and clinical characteristics of latent autoimmune diabetes in the elderly

Background: Latent autoimmune diabetes in adults (LADA) is determined by both a noninsulin-dependent clinical presentation and an autoimmune pathogenic process. Glutamic acid decarboxylase antibody (GADA) constitutes the most important marker, although IA-2A and ZnT8A also define LADA presentation. Type 2 diabetes mellitus (T2DM) is the most prevalent type particularly over 65 years old. Studies about autoimmunity in this age group are scarce. Objective: The aim of this work was to determine whether three autoantibodies for diabetes autoimmunity were present in elderly T2DM patients, and to assess the distinctive clinical features of autoantibody-positive patients. Research Design and Methods: We recruited 153 patients with diabetes with onset of diabetes after 65 years of age and a BMI under 30 kg/m2. Results: The prevalence of at least one of the autoantibodies was 15.68% (24/153). The most prevalent autoantibody was GADA with 8.49% (13/153), followed by ZnT8A with 6.50% (10/153) and IA2A with 1.96% (3/153). The autoimmunity-positive group presented higher HbA1c (7.01 ± 1.98 vs 6.35 ± 1.01; P = 0.007) and more prevalent insulin therapy (25% vs 10.85%; P = 0.047). GADA-positive patients with diabetes presented higher FPG (7.79 ± 3.79 mmol/L vs 6.43 ± 1.6 mmol/L; P = 0.014) and insulin therapy more frequently (46% vs 10.71%; p = 0.015). GADA titre levels in the individuals with BMI under 27 kg/m2 were higher (35.00 ± 4.20) than those in the group with BMI over 27 kg/m2 (8.83 ± 3.041; P = 0.0005). Conclusion:: Autoantibodies GADA and Znt8A may be useful markers in identifying a subgroup of older patients with a clinical presentation of diabetes which could be characterized as latent autoimmune diabetes in the elderly.Fil: Yohena, Silvina. Hospital Sirio Libanés; Argentina. Fundación Barceló. Instituto Universitario de Ciencias de la Salud; ArgentinaFil: Penas Steinhardt, Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Barceló. Instituto Universitario de Ciencias de la Salud; Argentina. Universidad Nacional de Luján; ArgentinaFil: Muller, Clara. Hospital Sirio Libanés; ArgentinaFil: Faccinetti, Natalia Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Cerrone, Gloria Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Lovecchio, Silvia. Hospital Sirio Libanés; Argentina. Fundación Barceló. Instituto Universitario de Ciencias de la Salud; ArgentinaFil: Ridner, Alberrto Edgardo. Fundación Barceló. Instituto Universitario de Ciencias de la Salud; ArgentinaFil: Valdez, Silvina Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Frechtel, Gustavo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Hospital Sirio Libanés; Argentina. Fundación Barceló. Instituto Universitario de Ciencias de la Salud; Argentin

Aberrant perineuronal nets alter spinal circuits, impair motor function, and increase plasticity

Altres ajuts: acords transformatius de la UABPerineuronal nets (PNNs) are a specialized extracellular matrix that have been extensively studied in the brain. Cortical PNNs are implicated in synaptic stabilization, plasticity inhibition, neuroprotection, and ionic buffering. However, the role of spinal PNNs, mainly found around motoneurons, is still unclear. Thus, the goal of this study is to elucidate the role of spinal PNNs on motor function and plasticity in both intact and spinal cord injured mice. We used transgenic mice lacking the cartilage link protein 1 (Crtl1 KO mice), which is implicated in PNN assembly. Crtl1 KO mice showed disorganized PNNs with an altered proportion of their components in both motor cortex and spinal cord. Behavioral and electrophysiological tests revealed motor impairments and hyperexcitability of spinal reflexes in Crtl1 KO compared to WT mice. These functional outcomes were accompanied by an increase in excitatory synapses around spinal motoneurons. Moreover, following spinal lesions of the corticospinal tract, Crtl1 KO mice showed increased contralateral sprouting compared to WT mice. Altogether, the lack of Crtl1 generates aberrant PNNs that alter excitatory synapses and change the physiological properties of motoneurons, overall altering spinal circuits and producing motor impairment. This disorganization generates a permissive scenario for contralateral axons to sprout after injury

Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis

Cerebellar neuronal progenitors undergo a series of divisions before irreversibly exiting the cell cycle and differentiating into neurons. Dysfunction of this process underlies many neurological diseases including ataxia and the most common pediatric brain tumor, medulloblastoma. To better define the pathways controlling the most abundant neuronal cells in the mammalian cerebellum, cerebellar granule cell progenitors (GCPs), we performed RNA-sequencing of GCPs exiting the cell cycle. Time-series modeling of GCP cell cycle exit identified downregulation of activity of the epigenetic reader protein Brd4. Brd4 binding to the Gli1 locus is controlled by Casein Kinase 1δ (CK1 δ)-dependent phosphorylation during GCP proliferation, and decreases during GCP cell cycle exit. Importantly, conditional deletion of Brd4 in vivo in the developing cerebellum induces cerebellar morphological deficits and ataxia. These studies define an essential role for Brd4 in cerebellar granule cell neurogenesis and are critical for designing clinical trials utilizing Brd4 inhibitors in neurological indications