Equipos virtuales en un clima creativo: habilidades, competencias y tecnología

El presente documento explora el estado del arte de los equipos de trabajo virtuales en el entorno global y pretende hacer un compendio de factores clave, procesos, herramientas y competencias identificadas al respecto por diversos autores

Efecto anti-tumoral de dos triterpenos aislados de una planta medicinal

Los ácidos masticadienónico (1) y 3α-OH masticadienoico (2) son los principales metabolitos secundarios aislados de la corteza de Amphipterygium adstringens. En trabajos previos se han investigado las propiedades biológicas de estos ácidos. Inicialmente, se demostró la actividad antiinflamatoria en dos modelos de inflamación aguda, carragenina y TPA (12-O-tetradecanoilphorbol-13- acetato) (Oviedo, 2004). Por otro lado, se demostró que estos compuestos inhiben la proliferación de las líneas celulares de cáncer humano (Oviedo, 2005). Respecto al mecanismo anti-tumoral recientemente se informó el efecto de 2 sobre las funciones bioenergéticas y la permeabilidad de la membrana mitocondrial (Dalla, 2012). Sin embargo, no se ha investigado su actividad anti-tumoral in vivo. En este trabajo se investigó el efecto de 1 y 2 sobre el crecimiento tumoral en un modelo murino. Los resultados de esta investigación demuestran que los ácidos 1 y 2 tienen un efecto anti-tumoral en xenotransplantes de carcinoma prostático.The masticadienonic acid (1) and 3α-OH masticadienoic acid (2) are the main secondary metabolites of the barck from Amphipterygium adstringens (Navarrete, 2006). In previous works, were investigated the biological properties of these acids. First, was demonstrated their anti-inflamatory activity by TPA (12-Otetradecanoylphorbol- 13-acetate) and carrageenan inflammatory acute models. Also, has been demonstrated that 1 and 2 compounds inhibit the proliferation of the human cancer cell lines, HCT-15 (colon), MCF-7 (breast), U-251 (CNS), PC-3 (prostate), K-562 (leukaemia), (Oviedo, 2005). Respect to the anti-tumor mechanism recently was informed the effect of 2 on bioenergetics functions and permeability of mithocondrial membrane (Dalla, 2012). However, there are no studies about anti-tumor activity of 1 and 2 in vivo. In this work we investigated the effect of 1 and 2 on growth tumor in a murine model. The results of this research showed that acids 1 and 2 have anti-tumor effect in xenografts of prostatic carcinoma

Psychometric characteristics of the Spanish version of instruments to measure neck pain disability

Background: The NDI, COM and NPQ are evaluation instruments for disability due to NP. There was no Spanish version of NDI or COM for which psychometric characteristics were known. The objectives of this study were to translate and culturally adapt the Spanish version of the Neck Disability Index Questionnaire (NDI), and the Core Outcome Measure (COM), to validate its use in Spanish speaking patients with non-specific neck pain (NP), and to compare their psychometric characteristics with those of the Spanish version of the Northwick Pain Questionnaire (NPQ). Methods: Translation/re-translation of the English versions of the NDI and the COM was done blindly and independently by a multidisciplinary team. The study was done in 9 primary care Centers and 12 specialty services from 9 regions in Spain, with 221 acute, subacute and chronic patients who visited their physician for NP: 54 in the pilot phase and 167 in the validation phase. Neck pain (VAS), referred pain (VAS), disability (NDI, COM and NPQ), catastrophizing (CSQ) and quality of life (SF-12) were measured on their first visit and 14 days later. Patients' self-assessment was used as the external criterion for pain and disability. In the pilot phase, patients' understanding of each item in the NDI and COM was assessed, and on day 1 test-retest reliability was estimated by giving a second NDI and COM in which the name of the questionnaires and the order of the items had been changed. Results: Comprehensibility of NDI and COM were good. Minutes needed to fill out the questionnaires [median, (P25, P75)]: NDI. 4 (2.2, 10.0), COM: 2.1 (1.0, 4.9). Reliability: [ICC, (95%CI)]: NDI: 0.88 (0.80, 0.93). COM: 0.85 (0.75,0.91). Sensitivity to change: Effect size for patients having worsened, not changed and improved between days 1 and 15, according to the external criterion for disability: NDI: -0.24, 0.15, 0.66; NPQ: -0.14, 0.06, 0.67; COM: 0.05, 0.19, 0.92. Validity: Results of NDI, NPQ and COM were consistent with the external criterion for disability, whereas only those from NDI were consistent with the one for pain. Correlations with VAS, CSQ and SF-12 were similar for NDI and NPQ (absolute values between 0.36 and 0.50 on day 1, between 0.38 and 0.70 on day 15), and slightly lower for COM (between 0.36 and 0.48 on day 1, and between 0.33 and 0.61 on day 15). Correlation between NDI and NPQ: r = 0.84 on day 1, r = 0.91 on day 15. Correlation between COM and NPQ: r = 0.63 on day 1, r = 0.71 on day 15. Conclusion: Although most psychometric characteristics of NDI, NPQ and COM are similar, those from the latter one are worse and its use may lead to patients' evolution seeming more positive than it actually is. NDI seems to be the best instrument for measuring NP-related disability, since its results are the most consistent with patient's assessment of their own clinical status and evolution. It takes two more minutes to answer the NDI than to answer the COM, but it can be reliably filled out by the patient without assistance

Molecular mechanism of the inhibition of TDP-43 amyloidogenesis by QBP1

Transactive Response DNA-Binding Protein of 43 kDa (TDP-43) is an essential human protein implicated in Amyotrophic Lateral Sclerosis (ALS) and common dementias. Its C-terminal disordered region, composed of residues 264–414 includes a hydrophobic segment (residues 320–340), which drives physiological liquid/liquid phase separation and a Q/N-rich segment (residues 341–357), which is essential for pathological amyloid formation. Due to TDP-43's relevance for pathology, identifying inhibitors and characterizing their mechanism of action are important pharmacological goals. The Polyglutamine Binding Peptide 1 (QBP1), whose minimal active core is the octapeptide WGWWPGIF, strongly inhibits the aggregation of polyQ-containing amyloidogenic proteins such as Huntingtin. Rather promiscuous, this inhibitor also blocks the aggregation of other glutamine containing amyloidogenic proteins, but not Aβ, and its mechanism of action remains unknown. Using a series of spectroscopic assays and biochemical tests, we establish that QBP1 binds and inhibits amyloid formation by TDP-43's Q/N-rich region. NMR spectroscopic data evince that the aromatic rings of QBP1 accept hydrogen bonds from the HN groups of the Asn and Gln to block amyloidogenesis. This mechanism of blockage may be general to polyphenol amyloid inhibitors.This study was supported by a Junior Leader Project LCF/BQ/PR19/11700003 (to MMG) from the Caixa Foundation (CID-100010434),and projects SAF2016-76678-C2-1-R (MC-V) and SAF2016-76678-C2-2-R(DVL) from the Spanish Ministry of Economy and Competitivity.NMR experiments were performed in the “Manuel Rico” NMR Laboratory (LMR) of the Spanish National Research Council (CSIC), a node of the Spanish Large-Scale National Facility (ICTSR-LRB)

Automatización de bobinadora de alambre

IM103 Bobinadora de alambr

Conformational dynamics in the disordered region of human CPEB3 linked to memory consolidation

Background: Current understanding of the molecular basis of memory consolidation points to an important function of amyloid formation by neuronal-specific isoforms of the cytoplasmic polyadenylation element binding (CPEB) protein family. In particular, CPEB is thought to promote memory persistence through formation of self-sustaining prion-like amyloid assemblies at synapses, mediated by its intrinsically disordered region (IDR) and leading to permanent physical alterations at the basis of memory persistence. Although the molecular mechanisms by which amyloid formation takes place in CPEB have been described in invertebrates, the way amyloid formation occurs in the human homolog CPEB3 (hCPEB3) remains unclear. Here, we characterize by NMR spectroscopy the atomic level conformation and ps-ms dynamics of the 426-residue IDR of hCPEB3, which has been associated with episodic memory in humans. Results: We show that the 426-residue N-terminal region of hCPEB3 is a dynamic, intrinsically disordered region (IDR) which lacks stable folded structures. The first 29 residues, MQDDLLMDKSKTQPQPQQQQRQQQQPQP, adopt a helical + disordered motif, and residues 86–93: PQQPPPP, and 166–175: PPPPAPAPQP form polyproline II (PPII) helices. The (VG) repeat motif is completely disordered, and residues 200–250 adopt three partially populated α-helices. Residues 345–355, which comprise the nuclear localization signal (NLS), form a modestly populated α-helix which may mediate STAT5B binding. These findings allow us to suggest a model for nascent hCPEB3 structural transitions at single residue resolution, advancing that amyloid breaker residues, like proline, are a key difference between functional versus pathological amyloids. Conclusion: Our NMR spectroscopic analysis of hCPEB3 provides insights into the first structural transitions involved in protein–protein and protein-mRNA interactions. The atomic level understanding of these structural transitions involved in hCPEB3 aggregation is a key first step toward understanding memory persistence in humans, as well as sequence features that differentiate beneficial amyloids from pathological ones. Areas: Biophysics, Structural Biology, Biochemistry & Neurosciences.This study was supported by projects SAF2016-76678-C2-1-R (MC-V) and SAF2016-76678-C2-2-R (DVL) from the Spanish Ministry of Economy and Competitivity (MINECO/AEI/FEDER, UE) and PID 2019-109306RB-I00/AEI/10.13039/501100011033 from the Spanish Ministry of Science and Innovation (DVL). The authors declare no competing interests

Expanded Conformations of Monomeric Tau Initiate Its Amyloidogenesis

11 pags., 5 figs.Understanding early amyloidogenesis is key to rationally develop therapeutic strategies. Tau protein forms well-characterized pathological deposits but its aggregation mechanism is still poorly understood. Using single-molecule force spectroscopy based on a mechanical protection strategy, we studied the conformational landscape of the monomeric tau repeat domain (tauRD244-368). We found two sets of conformational states, whose frequency is influenced by mutations and the chemical context. While pathological mutations Δ280K and P301L and a pro-amyloidogenic milieu favored expanded conformations and destabilized local structures, an anti-amyloidogenic environment promoted a compact ensemble, including a conformer whose topology might mask two amyloidogenic segments. Our results reveal that to initiate aggregation, monomeric tau-RD244-368 decreases its polymorphism adopting expanded conformations. This could account for the distinct structures found in vitro and across tauopathies.Spanish Agency for Research (AEI). Grant Numbers: SAF2016-76678-C2-1-R, SAF2016-76678-C2-2-R, BFU2015-70072-RPeer reviewe

Molecular basis of Orb2 amyloidogenesis and blockade of memory consolidation

Amyloids are ordered protein aggregates that are typically associated with neurodegenerative diseases and cognitive impairment. By contrast, the amyloid-like state of the neuronal RNA binding protein Orb2 in Drosophila was recently implicated in memory consolidation, but it remains unclear what features of this functional amyloid-like protein give rise to such diametrically opposed behaviour. Here, using an array of biophysical, cell biological and behavioural assays we have characterized the structural features of Orb2 from the monomer to the amyloid state. Surprisingly, we find that Orb2 shares many structural traits with pathological amyloids, including the intermediate toxic oligomeric species, which can be sequestered in vivo in hetero-oligomers by pathological amyloids. However, unlike pathological amyloids, Orb2 rapidly forms amyloids and its toxic intermediates are extremely transient, indicating that kinetic parameters differentiate this functional amyloid from pathological amyloids. We also observed that a well-known anti-amyloidogenic peptide interferes with long-term memory in Drosophila. These results provide structural insights into how the amyloid-like state of the Orb2 protein can stabilize memory and be nontoxic. They also provide insight into how amyloid-based diseases may affect memory processes.This research was supported by funds from SAF2013-49179-C2-1-R JPND_CD_FP-688- 059 (AC14/00037 ISCIII) to MCV, SIMR to KS, SAF2013-49179-C2-2-R JPND_CD_FP-688-059 (AC14/00037 ISCIII) to DVL, BFU2012-36825, S2011/BMD-2457 (Comunidad de Madrid)Peer Reviewe

Divergent CPEB prion-like domains reveal different assembly mechanisms for a generic amyloid-like fold

14 pags., 4 figs.Background: Amyloids are ordered, insoluble protein aggregates, characterized by a cross-β sheet quaternary structure in which molecules in a β-strand conformation are stacked along the filament axis via intermolecular interactions. While amyloids are typically associated with pathological conditions, functional amyloids have also been identified and are present in a wide variety of organisms ranging from bacteria to humans. The cytoplasmic polyadenylation element-binding (CPEB) prion-like protein is an mRNA-binding translation regulator, whose neuronal isoforms undergo activity-dependent aggregation, a process that has emerged as a plausible biochemical substrate for memory maintenance. CPEB aggregation is driven by prion-like domains (PLD) that are divergent in sequence across species, and it remains unknown whether such divergent PLDs follow a similar aggregating assembly pathway. Here, we describe the amyloid-like features of the neuronal Aplysia CPEB (ApCPEB) PLD and compare them to those of the Drosophila ortholog, Orb2 PLD. Results: Using in vitro single-molecule and bulk biophysical methods, we find transient oligomers and mature amyloid-like filaments that suggest similarities in the late stages of the assembly pathway for both ApCPEB and Orb2 PLDs. However, while prior to aggregation the Orb2 PLD monomer remains mainly as a random coil in solution, ApCPEB PLD adopts a diversity of conformations comprising α-helical structures that evolve to coiled-coil species, indicating structural differences at the beginning of their amyloid assembly pathways. Conclusion: Our results indicate that divergent PLDs of CPEB proteins from different species retain the ability to form a generic amyloid-like fold through different assembly mechanisms.The work was funded by two joint grants from the Ministry of Economy and Competitiveness to MCV (SAF2013-49179-C2-1-R and SAF2016-76678-C2-1-R) and DVL (SAF2013-49179-C2-2-R and SAF2016-76678-C2-2-R) and grants of the Ministry of Economy and Science (BFU2015-70072-R) and the CIBER de Enfermedades Respiratorias (CIBERES; ISCIII) to MM