Search

Transcription factors are among the most attractive therapeutic targets, but are considered largely undruggable. Here we provide evidence that small molecule-mediated partitioning of the androgen receptor, an oncogenic transcription factor, into phase-separated condensates has therapeutic effect in prostate cancer models. We show that the phase separation capacity of the androgen receptor is driven by aromatic residues and short unstable helices in its intrinsically disordered activation domain. Based on this knowledge, we developed tool compounds that covalently attach aromatic moieties to cysteines in the receptors’ activation domain. The compounds enhanced partitioning of the receptor into condensates, facilitated degradation of the receptor, inhibited androgen receptor-dependent transcriptional programs, and had antitumorigenic effect in models of prostate cancer and castration-resistant prostate cancer in vitro and in vivo. These results establish a generalizable framework to target the phase- separation capacity of intrinsically disordered regions in oncogenic transcription factors and other disease-associated proteins with therapeutic intent.

Objectives: The authors investigated the impact of coronary artery bypass grafting (CABG) on first and recurrent hospitalization in this population. Background: In the STICH (Surgical Treatment for Ischemic Heart Failure) trial, CABG reduced all-cause death and hospitalization in patients with and ischemic cardiomyopathy and left ventricular ejection fraction

Prion-like proteins form multivalent assemblies and phase separate into membraneless organelles. Heterogeneous ribonucleoprotein D-like (hnRNPDL) is a RNA-processing prion-like protein with three alternative splicing (AS) isoforms, which lack none, one, or both of its two disordered domains. It has been suggested that AS might regulate the assembly properties of RNA-processing proteins by controlling the incorporation of multivalent disordered regions in the isoforms. This, in turn, would modulate their activity in the downstream splicing program. Here, we demonstrate that AS controls the phase separation of hnRNPDL, as well as the size and dynamics of its nuclear complexes, its nucleus-cytoplasm shuttling, and amyloidogenicity. Mutation of the highly conserved D378 in the disordered C-terminal prion-like domain of hnRNPDL causes limb-girdle muscular dystrophy 1G. We show that D378H/N disease mutations impact hnRNPDL assembly properties, accelerating aggregation and dramatically reducing the protein solubility in the muscle of Drosophila, suggesting a genetic loss-of-function mechanism for this muscular disorder.

BACKGROUND: Around 1% of human proteins are predicted to contain a disordered and low complexity prion-like domain (PrLD). Mutations in PrLDs have been shown promote a transition towards an aggregation-prone state in several diseases. RESULTS: Recently, we have shown that an algorithm that considers the effects of mutations on PrLDs composition, as well as on localized amyloid propensity can predict the impact of these amino acid changes on protein intracellular aggregation. In this application note, we implement this concept into the AMYCO web server, a refined algorithm that forecasts the influence of amino acid changes in prion-like proteins aggregation propensity better than state-of-the-art predictors. CONCLUSIONS: The AMYCO web server allows for a fast and automated evaluation of the effect of mutations on the aggregation properties of prion-like proteins. This might uncover novel disease-linked amino acid changes in the sequences of human prion-like proteins. Additionally, it can find application in the in silico design of synthetic prion-like proteins with tuned aggregation propensities for different purposes. AMYCO does not require previous registration and is freely available to all users at: http://bioinf.uab.cat/amyco/ .

BACKGROUND/OBJECTIVES: The primary objective of this study was to explore physicians' adherence to the dietary pattern known as the Mediterranean diet (MD). As a secondary objective we assessed physicians' awareness on the benefits of the MD and of the possibility of prescribing it. SUBJECTS/METHODS: Physicians' adherence to the MD was evaluated through the Spanish associations SEMERGEN and CAMFIC, who sent the validated PREDIMED screener to their affiliates. The results reflected a high, medium, low or very low level of adherence depending on total score. The sample was drawn between 2014 and 2016. The second questionnaire evaluated the physicians' knowledge of the MD and their opinion about recommending it. RESULTS: The PREDIMED test was answered by 422 Spanish physicians. In 8 out of 14 questions, more than 50% of the individuals scored only 1 point. However, 3 questions resulted in 1 point being scored by almost all physicians. Thus, on average, 55% of questions obtained 1-point scoring. The second questionnaire was answered by 212 physicians; 70% of them considered themselves to be aware of the benefits of the MD. More than 60% said they could invest 5 min of their time to recommend the MD. CONCLUSIONS: Primary care physicians do not show a high level of adherence to the MD and emphasize the need for creating tools to evaluate it in their patients. This research can be useful as both a database and a justification for the creation of a new protocol to help physicians increase their own and their patients' MD adherence.

Prion-like behaviour is attracting much attention due to the growing evidences that amyloid-like self-assembly may reach beyond neurodegeneration and be a conserved functional mechanism. The best characterized functional prions correspond to a subset of yeast proteins involved in translation or transcription. Their conformational promiscuity is encoded in Prion Forming Domains (PFDs), usually long and intrinsically disordered protein segments of low complexity. The compositional bias of these regions seems to be important for the transition between soluble and amyloid-like states. We have proposed that the presence of cryptic soft amyloid cores embedded in yeast PFDs can also be important for their assembly and demonstrated their existence and self-propagating abilities. Here, we used an orthogonal approach in the search of human domains that share yeast PFDs compositional bias and exhibit a predicted nucleating core, identifying 535 prion-like candidates. We selected seven proteins involved in transcriptional or translational regulation and associated to disease to characterize the properties of their amyloid cores. All of them self-assemble spontaneously into amyloid-like structures able to propagate their polymeric state. This provides support for the presence of short sequences able to trigger conformational conversion in prion-like human proteins, potentially regulating their functionality.

The aberrant or misfolded forms of the prion protein have been described as the causative agents of rare transmissible spongiform encephalopathies. In addition, proteins associated with frequently occurring neurodegenerative disorders, such as Alzheimer's and Parkinson's, are shown to share prion-like properties and to spread the disease in the brain. Areas covered: Interest in the prion phenomenon has crystallized in a series of computational methods aimed at uncovering prion-like proteins at the proteome level. These programs rely on the identification of sequence signatures similar to those of yeast prions, whose structural conversion is driven by specific domains enriched in glutamine/asparagine residues. A myriad of prion-like candidates, similar to those in yeast, are predicted to exist in organisms across all kingdoms of life. We review here the role of prions, prionoids and prion-like proteins in health and disease, with a special focus on the algorithms and databases developed for their prediction and classification. Expert commentary: Computational approaches provide novel insights into prion-like protein functions, their regulation and their role in disease.

Despite the significant efforts devoted to decipher the particular protein features that encode for a prion or prion-like behavior, they are still poorly understood. The well-characterized yeast prions constitute an ideal model system to address this question, because, in these proteins, the prion activity can be univocally assigned to a specific region of their sequence, known as the prion forming domain (PFD). These PFDs are intrinsically disordered, relatively long and, in many cases, of low complexity, being enriched in glutamine/asparagine residues. Computational analyses have identified a significant number of proteins having similar domains in the human proteome. The compositional bias of these regions plays an important role in the transition of the prions to the amyloid state. However, it is difficult to explain how composition alone can account for the formation of specific contacts that position correctly PFDs and provide the enthalpic force to compensate for the large entropic cost of immobilizing these domains in the initial assemblies. We have hypothesized that short, sequence-specific, amyloid cores embedded in PFDs can perform these functions and, accordingly, act as preferential nucleation centers in both spontaneous and seeded aggregation. We have shown that the implementation of this concept in a prediction algorithm allows to score the prion propensities of putative PFDs with high accuracy. Recently, we have provided experimental evidence for the existence of such amyloid cores in the PFDs of Sup35, Ure2, Swi1, and Mot3 yeast prions. The fibrils formed by these short stretches may recognize and promote the aggregation of the complete proteins inside cells, being thus a promising tool for targeted protein inactivation.

Amyloids consist of repetitions of a specific polypeptide chain in a regular cross-ß-sheet conformation. Amyloid propensity is largely determined by the protein sequence, the aggregation process being nucleated by specific and short segments. Prions are special amyloids that become self-perpetuating after aggregation. Prions are responsible for neuropathology in mammals, but they can also be functional, as in yeast prions. The conversion of these last proteins to the prion state is driven by prion forming domains (PFDs), which are generally large, intrinsically disordered, enriched in glutamines/asparagines and depleted in hydrophobic residues. The self-assembly of PFDs has been thought to rely mostly on their particular amino acid composition, rather than on their sequence. Instead, we have recently proposed that specific amyloid-prone sequences within PFDs might be key to their prion behaviour. Here, we demonstrate experimentally the existence of these amyloid stretches inside the PFDs of the canonical Sup35, Swi1, Mot3 and Ure2 prions. These sequences self-assemble efficiently into highly ordered amyloid fibrils, that are functionally competent, being able to promote the PFD amyloid conversion in vitro and in vivo. Computational analyses indicate that these kind of amyloid stretches may act as typical nucleating signals in a number of different prion domains.

Podeu consultar la Vuitena trobada de professorat de Ciències de la Salut completa a: http://hdl.handle.net/2445/66524, La notificación de toda nueva formulación cosmética al CPNP es obligatoria para poder proceder a su producción y posterior comercialización a nivel europeo. Dicha notificación es informática e implica cumplimentar una información completa acerca de ingredientes, formulación, aspectos legales, etc. en base a las especificaciones legales fijads por el Reglamento Europeo de productos cosméticos (CE1223/2009, DOUE nº342, de 22/12). El acceso a dicho portal implica el registro de la empresa productora del cosmético. Por ello y afin de que los estudiantes de tercer ciclo puedan practicar simulaciones de comunicación al CPNP, guiadas y comentadas por parte de tutores expertos, cuestión que les resultará de gran utilidad en el dia a dia de la actividad profesional para la que se están formando, se propuso al Area Funcional de Sanidad de la Subdelegación del Gobierno en Cataluña, la consecución de un acceso como empresa de elaboración de cosméticos simulada, a nombre de Facultad de Farmacia de la Universidad de Barcelona para el acceso a dicho aplicativo. Ello ha permitido la realización de una sesión práctica en la que se siguen paso a paso las diferentes etapas de la notificación para un ejemplo propuesto por el profesor, y ha permitido la práctica individualizada por parte de los 18 alumnos de la actual promoción del Máster de diferentes casos reales, lo que sirve de “reválida” de los conocimientos adquiridos en las diferentes áreas formativas, cuyo fin es el de capacitar a dichos estudiantes para poder realizar la totalidad de las etapas de I+D de un cosmético, que obviamente concluyen con la comunicación del mismo al CPNP. Este es asimismo el objetivo que se les plantea para la realización y valoración de sus correspondientes proyectos finales.

Despite major efforts devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the amino acid sequence. In recent years, experimental data on yeast prion domains allow to start at least partially decrypting the sequence requirements of prion formation. These experiments illustrate the need for intrinsically disordered sequence regions enriched with a particularly high proportion of glutamine and asparagine. Bioinformatic analysis suggests that these regions strike a balance between sufficient amyloid nucleation propensity on the one hand and disorder on the other, which ensures availability of the amyloid prone regions but entropically prevents unwanted nucleation and facilitates brittleness required for propagation.

L'objectiu bàsic del projecte és augmentar significativament les capacitats d'autoaprenentatge dels estudiants de les assignatures de Matemàtiques del primer curs dels graus en enginyeria. El programari SAGE i els materials interactius creats haurien de cobrir aquest aspecte i alhora fer més atractiu l'estudi de les Matemàtiques als estudiants.

The role of coronary-artery bypass grafting (CABG) in the treatment of patients with coronary artery disease and heart failure has not been clearly established.Between July 2002 and May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomly assigned to medical therapy alone (602 patients) or medical therapy plus CABG (610 patients). The primary outcome was the rate of death from any cause. Major secondary outcomes included the rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes.The primary outcome occurred in 244 patients (41%) in the medical-therapy group and 218 (36%) in the CABG group (hazard ratio with CABG, 0.86; 95% confidence interval [CI], 0.72 to 1.04; P=0.12). A total of 201 patients (33%) in the medical-therapy group and 168 (28%) in the CABG group died from an adjudicated cardiovascular cause (hazard ratio with CABG, 0.81; 95% CI, 0.66 to 1.00; P=0.05). Death from any cause or hospitalization for cardiovascular causes occurred in 411 patients (68%) in the medical-therapy group and 351 (58%) in the CABG group (hazard ratio with CABG, 0.74; 95% CI, 0.64 to 0.85; P

In this Chapter we present some detailed examples of modelling in several domains using port and port-Hamiltonian concepts, as have been presented in the previous chapters. We start with the electromechanical domain in Sect. 3.1, while in Sect. 3.2 it is shown how port-Hamiltonian systems can be fruitfully used for the structured modelling of robotics mechanisms. In Sect. 3.3, it is show how to model simple elastic systems either in the Lagrangian and Hamiltonian framework, while, in Sect. 3.4, an expressions of the models representing momentum, heat and mass transfer as well as chemical reactions within homogeneous fluids in the port-based formalism is proposed. To this end, the entropy balance and the associated source terms are systematically written in accordance with the principle of irreversible thermodynamics. Some insights are also given concerning the constitutive equations and models allowing to calculate transport and thermodynamic properties. As it will be shown, for each physical domain, these port-based models can be translated into bond-graph models, in the case of distributed as well as lumped parameters models.