Observation of Replica Symmetry Breaking in the 1D Anderson Localization Regime in an Erbium-Doped Random Fiber Laser

The analogue of the paramagnetic to spin-glass phase transition in disordered magnetic systems, leading to the phenomenon of replica symmetry breaking, has been recently demonstrated in a two-dimensional random laser consisting of an organic-based amorphous solid-state thin film. We report here the first demonstration of replica symmetry breaking in a one-dimensional photonic system consisting of an erbium-doped random fiber laser operating in the continuous-wave regime based on a unique random fiber grating system, which plays the role of the random scatterers and operates in the Anderson localization regime. The clear transition from a photonic paramagnetic to a photonic spin glass phase, characterized by the probability distribution function of the Parisi overlap, was verified and characterized. In this unique system, the radiation field interacts only with the gain medium, and the fiber grating, which provides the disordered feedback mechanism, does not interfere with the pump

Clonamiento y expresion del canal de cloruro CI-5 en epitelio intestinal de cobayo

71 p.Los canales de cloruro están presentes en la membrana celular de todas las células y en organelos intracelulares cumpliendo diferentes funciones. Algunos de estos canales han sido identificados molecularmente siendo la familia de canales de cloruro activados por voltaje o C1C la más numerosa. Hasta ahora, se han identificado 9 miembros de esta familia en mamíferos, estando establecida la función solamente para algunos de ellos. Además, mutaciones en algunos de estos canales han revelado ser causa de patologías humanas. Es así, como la enfermedad de Dent, caracterizada por proteinuria de bajo peso molecular y nefrolitiasis hipercalciúrica, es causada por mutaciones en el gen que codifica para el canal C1C-5. Estos hallazgos, previos al conocimiento de la función de este canal, han despertado gran interés en dilucidar los mecanismos por los que alteraciones en un canal de cloruro pueden generar un fenotipo caracterizado por proteinuria e hipercalciuria. Estudios de la presencia del RNA mensajero y de la proteína en diferentes especies coinciden en que la mayor expresión de C1C-5 ocurre en el riñón. En las células del túbulo proximal del nefrón C1C-5 se ubica intracelularmente en la membrana de vesículas endociticas tempranas, colocalizando con la bomba protón ATPasa vacuolar. De esta manera, el funcionamiento adecuado de este canal aniónico es necesario para lograr la acidificación intravesicular óptima requerida para la reabsorción de proteínas. Mutaciones en el gen que codifica a C1C-5, han demostrado causar ausencia o déficit en la actividad del canal, lo cual origina una falla en la disipación de cargas en las vesículas alterando la acidificación intravesicular y por ende la reabsorción de proteínas generando así proteinuria. Sin embargo, los mecanismos que llevan a la hipercalciuria en esta enfermedad son menos conocidos. Una hipótesis plantea que los cambios en el metabolismo del calcio son secundarios al trastorno de la endocitosis en el túbulo proximal. Alternativamente se ha sugerido que la hiperacalciuria seria secundaria a un aumento en la absorción intestinal de calcio. Considerando que el riñón no es el único órgano que participa en el metabolismo de proteínas y de calcio, se estudió la expresión del RNA mensajero de C1C-5 en el intestino delgado, órgano esencial en la absorción de ambos nutrientes desde la dieta. Además, existen antecedentes de que en el epitelio intestinal ocurre transporte vesicular tanto de proteínas como de calcio, lo cual hace más interesante estudiar la expresión de este canal en este órgano para posteriormente determinar cuál seria el papel fisiológico de C1C-5 en este tejido epitelial. En esta tesis se describe el clonamiento por homología del canal C1C-5 desde epitelio intestinal de cobayo mediante reacción en cadena de la polimerasa (PCR) y la distribución de su RNA mensajero en duodeno, yeyuno e ileon de cobayo. Para el clonamiento se utilizaron partidores apropiados con los que se obtuvo una secuencia parcial de 1144 pares de bases y los extremos 5 y 3 prima se obtuvieron mediante la técnica de amplificación rápida de los extremos de cDNA (RACE). Finalmente con partidores específicos diseñados a partir de las regiones 5 y 3 prima no traducidas se amplificó DNA complementario (cDNA), mediante la reacción de transcripción reversa del RNA obtenido del epitelio duodenal. Como resultado del clonamiento se obtuvo un cDNA cuya secuencia predice una proteína de 746 aminoácidos con un mínimo de un 95% de identidad con sus homólogos de otras especies. El análisis de hidrofobicidad de la secuencia aminoacídica, predice 10 a 12 dominios de transmembrana los cuales son comunes en todos los miembros de la familia C1C. Se detectaron sitios putativos de glicosilación y fosforilación por PKA y PKC que también han sido descritos en su homólogo de rata. La presencia del RNA mensajero en epitelio intestinal se estudió mediante transcripción reversa seguida de PCR (RT-PCR), Northern blot e Hibridación in situ. Mediante RTPCR se estableció la presencia del transcrito en las 3 porciones estudiadas. Mediante el análisis de Northern blot además de comprobar lo anterior, se estableció el tamaño del principal transcrito en aproximadamente 9,5 kilobases, equivalente a lo descrito en otras especies. Finalmente, la localización del mensajero se estudió mediante hibridación in situ utilizando una sonda de 662 pares de bases sintetizada por transcripción in vitro marcada con digoxigenina. Con esta técnica se demostró la presencia del mensajero de C1C-5 en las células del epitelio que conforman tanto las criptas como las vellosidades del duodeno yeyuno e ileon. La localización del RNA mensajero exclusivamente en las células epiteliales del intestino delgado sugiere la posible participación de este canal en el transporte transepitelial lo cual debe ser resuelto mediante futuros estudios

Sexual Dimorphism and Estrogen Regulation of KCNE3 Expression Modulates the Functional Properties of KCNQ1 K+ Channels

The KCNQ1 potassium channel associates with various KCNE ancillary subunits that drastically affect channel gating and pharmacology. Co-assembly with KCNE3 produces a current with nearly instantaneous activation, some time-dependent activation at very positive potentials, a linear current voltage relationship and a 10-fold higher sensitivity to chromanol 293B. KCNQ1:KCNE3 channels are expressed in colonic crypts and mediate basolateral K+ recycling required for Cl- secretion. We have previously reported the female-specific anti-secretory effects of estrogen via KCNQ1:KCNE3 channel inhibition in colonic crypts. This study was designed to determine whether gender and estrogen regulate the expression and function of KCNQ1 and KCNE3 in rat distal colon. Colonic crypts were isolated from Sprague-Dawley rats and used for whole-cell patch-clamp and to extract total RNA and protein. Sheets of epithelium were used for short-circuit current recordings. KCNE1 and KCNE3 mRNA and protein abundance was significantly higher in male than female crypts. No expression of KCNE2 was found and no difference was observed in KCNQ1 expression between male and female (at estrous) colonic crypts. Male crypts showed a 2.2-fold higher level of association of KCNQ1 and KCNE3 compared to female cells. In female colonic crypts, KCNQ1 and KCNE3 protein expression fluctuated throughout the estrous cycle and 17-estradiol (E2 10 nM) produced a rapid (\u3c15\u3emin) dissociation of KCNQ1 and KCNE3 in female crypts only. Whole-cell K+ currents showed a linear current-voltage relationship in male crypts, while K+ currents in colonic crypts isolated from females displayed voltage-dependent outward rectification. Currents in isolated male crypts and epithelial sheets were 10-fold more sensitive to specific KCNQ1 inhibitors, such as chromanol 293B and HMR-1556, than in female. The effect of E2 on K+ currents mediated by KCNQ1 with or without different -subunits was assayed from current-voltage relations elicited in CHO cells transfected with KCNQ1 and KCNE3 or KCNE1 cDNA. E2 (100 nM) reduced the currents mediated by the KCNQ1:KCNE3 potassium channel and had no effect on currents via KCNQ1:KCNE1 or KCNQ1 alone. Currents mediated by the complex formed by KCNQ1 and the mutant KCNE3-S82A β-subunit showed rapid run-down and insensitivity to E2. Together, these data suggest that estrogen regulates the expression of the KCNE1 and KCNE3 and with it the gating and pharmacological properties of the K+ conductance required for Cl- secretion. The decreased association of the KCNQ1:KCNE3 channel complex promoted by estrogen exposure underlies the molecular mechanism for the sexual dimorphism and estrous cycle dependence of the anti-secretory actions of estrogen in the intestine

Open string wavefunctions in flux compactifications

We consider compactifications of type I supergravity on manifolds with SU(3) structure, in the presence of RR fluxes and magnetized D9-branes, and analyze the generalized Dirac and Laplace-Beltrami operators associated to the D9-brane worldvolume fields. These compactifications are T-dual to standard type IIB toroidal orientifolds with NSNS and RR 3-form fluxes and D3/D7 branes. By using techniques of representation theory and harmonic analysis, the spectrum of open string wavefunctions can be computed for Lie groups and their quotients, as we illustrate with explicit twisted tori examples. We find a correspondence between irreducible unitary representations of the Kaloper-Myers algebra and families of Kaluza-Klein excitations. We perform the computation of 2- and 3-point couplings for matter fields in the above flux compactifications, and compare our results with those of 4d effective supergravity.Comment: 89 pages, 4 figures. v3: more typos corrected, version published in JHE

Cryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain

Kv3 channels have distinctive gating kinetics tailored for rapid repolarization in fast-spiking neurons. Malfunction of this process due to genetic variants in the KCNC1 gene causes severe epileptic disorders, yet the structural determinants for the unusual gating properties remain elusive. Here, we present cryo-electron microscopy structures of the human Kv3.1a channel, revealing a unique arrangement of the cytoplasmic tetramerization domain T1 which facilitates interactions with C-terminal axonal targeting motif and key components of the gating machinery. Additional interactions between S1/S2 linker and turret domain strengthen the interface between voltage sensor and pore domain. Supported by molecular dynamics simulations, electrophysiological and mutational analyses, we identify several residues in the S4/S5 linker which influence the gating kinetics and an electrostatic interaction between acidic residues in α6 of T1 and R449 in the pore-flanking S6T helices. These findings provide insights into gating control and disease mechanisms and may guide strategies for the design of pharmaceutical drugs targeting Kv3 channels

Gating of a pH-Sensitive K 2P Potassium Channel by an Electrostatic Effect of Basic Sensor Residues on the Selectivity Filter

Abstract K + channels share common selectivity characteristics but exhibit a wide diversity in how they are gated open. Leak K 2P K + channels TASK-2, TALK-1 and TALK-2 are gated open by extracellular alkalinization. The mechanism for this alkalinizationdependent gating has been proposed to be the neutralization of the side chain of a single arginine (lysine in TALK-2) residue near the pore of TASK-2, which occurs with the unusual pK a of 8.0. We now corroborate this hypothesis by transplanting the TASK-2 extracellular pH (pH o ) sensor in the background of a pH o -insensitive TASK-3 channel, which leads to the restitution of pH o -gating. Using a concatenated channel approach, we also demonstrate that for TASK-2 to open, pH o sensors must be neutralized in each of the two subunits forming these dimeric channels with no apparent cross-talk between the sensors. These results are consistent with adaptive biasing force analysis of K + permeation using a model selectivity filter in wild-type and mutated channels. The underlying free-energy profiles confirm that either a doubly or a singly charged pH o sensor is sufficient to abolish ion flow. Atomic detail of the associated mechanism reveals that, rather than a collapse of the pore, as proposed for other K 2P channels gated at the selectivity filter, an increased height of the energetic barriers for ion translocation accounts for channel blockade at acid pH o . Our data, therefore, strongly suggest that a cycle of protonation/deprotonation of pH o -sensing arginine 224 side chain gates the TASK-2 channel by electrostatically tuning the conformational stability of its selectivity filter

Supramolecular Hydrogels Consisting of Nanofibers Increase the Bioavailability of Curcuminoids in Inflammatory Skin Diseases

The low bioavailability of curcuminoids (CCMoids) limits their use in the treatment of inflammatory skin diseases. Our work shows that this constraint can be overcome upon their incorporation into supramolecular hydrogels assembled from a gemini-imidazolium amphiphilic gelator. Three structural CCMoid analogues were used to prepare supramolecular hydrogels, and it was observed that the concentration of both the gelator and CCMoid and the proportion of solvents influence the self-assembly process. Moreover, the mechanical properties of the nanostructured gels were studied to find the optimum gels, which were then further characterized microscopically, and their ability to release the CCMoid was evaluated. The physicochemical properties of the CCMoids play a fundamental role in the interaction with the gelator, influencing not only the gelation but also the morphology at the microscopic level, the mechanical properties, and the biopharmaceutical behavior such as the amount of CCMoid released from the gels. The nanostructured supramolecular hydrogels, which contain the CCMoids at much lower concentrations (μg/mL) in comparison to other products, promote the penetration of the CCMoids within the skin, but not their transdermal permeation, thus preventing any possible systemic effects and representing a safer option for topical administration. As a result, the CCMoid-containing hydrogels can effectively reduce skin inflammation in vivo, proving that these supramolecular systems are excellent alternatives in the treatment of inflammatory skin diseases.This work was supported by the projects PID2020-115663GB-C3-2, PID2019-108794GB-I00, and PID2020–115631GB-I00 funded by MCIN/AEI/10.13039/501100011033 from the Ministerio de Ciencia e Innovación. We thank AGAUR for a grant to consolidated research groups 2017SGR1277. A.G.-C. and N.A.-A. acknowledge the financial support from the Spanish Ministry Science, through the “Severo Ochoa” Programme for Centres of Excellence (FUNFUTURE) (2020-2023). A.G.-C. also acknowledges a Ramon y Cajal Grant (RYC-2017-22910).With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).Peer reviewe

2015 recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative

Therapy for polymyalgia rheumatica (PMR) varies widely in clinical practice as international recommendations for PMR treatment are not currently available. In this paper, we report the 2015 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) recommendations for the management of PMR. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology as a framework for the project. Accordingly, the direction and strength of the recommendations are based on the quality of evidence, the balance between desirable and undesirable effects, patients'and clinicians'values and preferences, and resource use. Eight overarching principles and nine specific recommendations were developed covering several aspects of PMR, including basic and follow-up investigations of patients under treatment, risk factor assessment, medical access for patients and specialist referral, treatment strategies such as initial glucocorticoid (GC) doses and subsequent tapering regimens, use of intramuscular GCs and disease modifying anti-rheumatic drugs (DMARDs), as well as the roles of non-steroidal anti-rheumatic drugs and non-pharmacological interventions. These recommendations will inform primary, secondary and tertiary care physicians about an international consensus on the management of PMR. These recommendations should serve to inform clinicians about best practices in the care of patients with PMR