Functional EF-hands in neuronal calcium sensor GCAP2 determine its phosphorylation state and subcellular distribution in vivo, and are essential for photoreceptor cell integrity

The neuronal calcium sensor proteins GCAPs (guanylate cyclase activating proteins) switch between Ca2+-free and Ca2+-bound conformational states and confer calcium sensitivity to guanylate cyclase at retinal photoreceptor cells. They play a fundamental role in light adaptation by coupling the rate of cGMP synthesis to the intracellular concentration of calcium. Mutations in GCAPs lead to blindness. The importance of functional EF-hands in GCAP1 for photoreceptor cell integrity has been well established. Mutations in GCAP1 that diminish its Ca2+ binding affinity lead to cell damage by causing unabated cGMP synthesis and accumulation of toxic levels of free cGMP and Ca2+. We here investigate the relevance of GCAP2 functional EF-hands for photoreceptor cell integrity. By characterizing transgenic mice expressing a mutant form of GCAP2 with all EF-hands inactivated (EF(-)GCAP2), we show that GCAP2 locked in its Ca2+-free conformation leads to a rapid retinal degeneration that is not due to unabated cGMP synthesis. We unveil that when locked in its Ca2+-free conformation in vivo, GCAP2 is phosphorylated at Ser201 and results in phospho-dependent binding to the chaperone 14-3-3 and retention at the inner segment and proximal cell compartments. Accumulation of phosphorylated EF(-)GCAP2 at the inner segment results in severe toxicity. We show that in wildtype mice under physiological conditions, 50% of GCAP2 is phosphorylated correlating with the 50% of the protein being retained at the inner segment. Raising mice under constant light exposure, however, drastically increases the retention of GCAP2 in its Ca2+-free form at the inner segment. This study identifies a new mechanism governing GCAP2 subcellular distribution in vivo, closely related to disease. It also identifies a pathway by which a sustained reduction in intracellular free Ca2+ could result in photoreceptor damage, relevant for light damage and for those genetic disorders resulting in 'equivalent-light'' scenarios.

Appropriate IPRs, Human Capital Composition and Economic Growth

We generalize a standard technology diffusion model by allowing for IPRs regimes to be endogenously defined by the development level of each country. Also we insert differences in the composition of human capital between North (leader) and South (followers) which shape the relative costs of innovation and imitation. Results show how an optimal growth trajectory is found for the follower country which initially imitates and that, once a "threshold development stage" is reached, optimally switches to innovation by fully enforcing IPRs achieving a higher proximity with the technology frontier in the long-run. Other scenarios, such as a premature increase in the enforcement of IPRs or a switch from imitation to innovation at early stages of development of the followers are found to be sub-optimal.

The L-type voltage-gated calcium channel modulates microglial pro-inflammatory activity

Under pathological conditions, microglia, the resident CNS immune cells, become reactive and release pro-inflammatory cytokines and neurotoxic factors. We investigated whether this phenotypic switch includes changes in the expression of the L-type voltage-gated calcium channel (VGCC) in a rat model of N-methyl-d-aspartate-induced hippocampal neurodegeneration. Double immunohistochemistry and confocal microscopy evidenced that activated microglia express the L-type VGCC. We then analyzed whether BV2 microglia express functional L-type VGCC, and investigated the latter's role in microglial cytokine release and phagocytic capacity. Activated BV2 microglia express the CaV1.2 and CaV1.3 subunits of the L-type VGCC determined by reverse transcription-polymerase chain reaction, Western blot and immunocytochemistry. Depolarization with KCl induced a Ca2+ entry facilitated by Bay k8644 and partially blocked with nifedipine, which also reduced TNF-α and NO release by 40%. However, no nifedipine effect on BV2 microglia viability or phagocytic capacity was observed. Our results suggest that in CNS inflammatory processes, the L-type VGCC plays a specific role in the control of microglial secretory activity.

Optimal Traffic Grooming in WDM using Lighttours

Recent developments in optical communications have allowed simpler optical devices to improve network resource utilization. As such, we propose adding a lambda-monitoring device to a wavelength-routing switch (WRS) allowing better performance when traffic is routed and groomed. This device may allow a WRS to aggregate traffic over optical routes without incurring in optical-electrical-optical conversion for the existing traffic. In other words, optical routes can be taken partially to route demands creating a sort of "lighttours". In this paper, we compare the number of OEO conversions needed to route a complete given traffic matrix using either lighttours or lightpaths

G+: Enhanced Traffic Grooming in WDM Mesh Networks using Lighttours

In this article, a new technique for grooming low-speed traffic demands into high-speed optical routes is proposed. This enhancement allows a transparent wavelength-routing switch (WRS) to aggregate traffic en route over existing optical routes without incurring expensive optical-electrical-optical (OEO) conversions. This implies that: a) an optical route may be considered as having more than one ingress node (all inline) and, b) traffic demands can partially use optical routes to reach their destination. The proposed optical routes are named "lighttours" since the traffic originating from different sources can be forwarded together in a single optical route, i.e., as taking a "tour" over different sources towards the same destination. The possibility of creating lighttours is the consequence of a novel WRS architecture proposed in this article, named "enhanced grooming" (G+). The ability to groom more traffic in the middle of a lighttour is achieved with the support of a simple optical device named lambda-monitor (previously introduced in the RingO project). In this article, we present the new WRS architecture and its advantages. To compare the advantages of lighttours with respect to classical lightpaths, an integer linear programming (ILP) model is proposed for the well-known multilayer problem: traffic grooming, routing and wavelength assignment The ILP model may be used for several objectives. However, this article focuses on two objectives: maximizing the network throughput, and minimizing the number of optical-electro-optical conversions used. Experiments show that G+ can route all the traffic using only half of the total OEO conversions needed by classical grooming. An heuristic is also proposed, aiming at achieving near optimal results in polynomial time

Self-assessment of individual differences in language switching

Language switching is omnipresent in bilingual individuals. In fact, the ability to switch languages (code switching) is a very fast, efficient, and flexible process that seems to be a fundamental aspect of bilingual language processing. In this study, we aimed to characterize psychometrically self-perceived individual differences in language switching and to create a reliable measure of this behavioral pattern by introducing a bilingual switching questionnaire. As a working hypothesis based on the previous literature about code switching, we decomposed language switching into four constructs: (i) L1 switching tendencies (the tendency to switch to L1; L1-switch); (ii) L2 switching tendencies (L2-switch); (iii) contextual switch, which indexes the frequency of switches usually triggered by a particular situation, topic, or environment; and (iv) unintended switch, which measures the lack of intention and awareness of the language switches. A total of 582 SpanishCatalan bilingual university students were studied. Twelve items were selected (three for each construct). The correlation matrix was factor-analyzed using minimum rank factor analysis followed by oblique direct oblimin rotation. The overall proportion of common variance explained by the four extracted factors was 0.86. Finally, to assess the external validity of the individual differences scored with the new questionnaire, we evaluated the correlations between these measures and several psychometric (language proficiency) and behavioral measures related to cognitive and attentional control. The present study highlights the importance of evaluating individual differences in language switching using self-assessment instruments when studying the interface between cognitive control and bilingualism.

First- and second-language phonological representations in the mental lexicon

Performance-based studies on the psychological nature of linguistic competence can conceal significant differences in the brain processes that underlie native versus nonnative knowledge of language. Here we report results from the brain activity of very proficient early bilinguals making a lexical decision task that illustrates this point. Two groups of SpanishCatalan early bilinguals (Spanish-dominant and Catalan-dominant) were asked to decide whether a given form was a Catalan word or not. The nonwords were based on real words, with one vowel changed. In the experimental stimuli, the vowel change involved a Catalan-specific contrast that previous research had shown to be difficult for Spanish natives to perceive. In the control stimuli, the vowel switch involved contrasts common to Spanish and Catalan. The results indicated that the groups of bilinguals did not differ in their behavioral and event-related brain potential measurements for the control stimuli; both groups made very few errors and showed a larger N400 component for control nonwords than for control words. However, significant differences were observed for the experimental stimuli across groups: Specifically, Spanish-dominant bilinguals showed great difficulty in rejecting experimental nonwords. Indeed, these participants not only showed very high error rates for these stimuli, but also did not show an error-related negativity effect in their erroneous nonword decisions. However, both groups of bilinguals showed a larger correctrelated negativity when making correct decisions about the experimental nonwords. The results suggest that although some aspects of a second language system may show a remarkable lack of plasticity (like the acquisition of some foreign contrasts), first-language representations seem to be more dynamic in their capacity of adapting and incorporating new information. &

Clinical consequences of switching from olanzapine to risperidone and vice versa in outpatients with schizophrenia: 36-month results from the worldwide schizophrenia outpatients health outcomes (W-SOHO) study

BACKGROUND: With many atypical antipsychotics now available in the market, it has become a common clinical practice to switch between atypical agents as a means of achieving the best clinical outcomes. This study aimed to examine the impact of switching from olanzapine to risperidone and vice versa on clinical status and tolerability outcomes in outpatients with schizophrenia in a naturalistic setting. METHODS: W-SOHO was a 3-year observational study that involved over 17,000 outpatients with schizophrenia from 37 countries worldwide. The present post hoc study focused on the subgroup of patients who started taking olanzapine at baseline and subsequently made the first switch to risperidone (n=162) and vice versa (n=136). Clinical status was assessed at the visit when the first switch was made (i.e. before switching) and after switching. Logistic regression models examined the impact of medication switch on tolerability outcomes, and linear regression models assessed the association between medication switch and change in the Clinical Global Impression-Schizophrenia (CGI-SCH) overall score or change in weight. In addition, Kaplan-Meier survival curves and Cox-proportional hazards models were used to analyze the time to medication switch as well as time to relapse (symptom worsening as assessed by the CGI-SCH scale or hospitalization). RESULTS: 48% and 39% of patients switching to olanzapine and risperidone, respectively, remained on the medication without further switches (p=0.019). Patients switching to olanzapine were significantly less likely to experience relapse (hazard ratio: 3.43, 95% CI: 1.43, 8.26), extrapyramidal symptoms (odds ratio [OR]: 4.02, 95% CI: 1.49, 10.89) and amenorrhea/galactorrhea (OR: 8.99, 95% CI: 2.30, 35.13). No significant difference in weight change was, however, found between the two groups. While the CGI-SCH overall score improved in both groups after switching, there was a significantly greater change in those who switched to olanzapine (difference of 0.29 points, p=0.013). CONCLUSION: Our study showed that patients who switched from risperidone to olanzapine were likely to experience a more favorable treatment course than those who switched from olanzapine to risperidone. Given the nature of observational study design and small sample size, additional studies are warranted.

Eficiència energètica aplicada a les instal·lacions de la Universitat de Vic

En termes generals, es pot definir l’Eficiència Energètica com la reducció del consum d’energia mantenint els mateixos serveis energètics, sense disminuir el nostre confort i qualitat de vida, protegint el medi ambient, assegurant el proveïment i fomentant un comportament Sostenible al seu ús. L’objectiu principal d’aquest treball, és reduir el consum d’energia i terme de potència contractat a la Universitat de Vic, aplicant un programa d’estalvi amb mesures correctores en el funcionament de les seves instal·lacions o espais. Per tal de poder arribar a aquest objectiu marcat, prèviament s’ha realitzat un estudi acurat, obtenint tota la informació necessària per poder aplicar les mesures correctores a la bossa més important de consum. Un cop trobada, dur a terme l’estudi de la viabilitat de la inversió de les mesures correctores més eficients, optimitzant els recursos destinats. L’espai on s’ha dut a terme l’estudi, ha estat a l’edifici F del Campus Miramarges, seguint les indicacions d’Arnau Bardolet (Cap de Manteniment de la UVIC). Aquest edifici consta d’un entresol, baixos i quatre plantes. L’equip de mesura que s’ha fet servir per realitzar l’estudi, és de la marca Circutor sèrie AR5-L, aquests equips són programables que mesuren, calculen i emmagatzemen en memòria els principals paràmetres elèctrics en xarxes trifàsiques. Els projectes futurs complementaris que es podrien realitzar a part d’aquest són: instal·lar sensors, instal·lar mòduls convertidors TCP/IP, aprofitar la xarxa intranet i crear un escada amb un sinòptic de control i gestió des d’un punt de treball. Aquest aplicatiu permet visualitzar en una pantalla d’un PC tots els estats dels elements controlats mitjançant un sinòptic (encendre/parar manualment l’enllumenat i endolls de les aules, estat d’enllumenat i endolls de les aules, consums instantanis/acumulats energètics, estat dels passadissos entre altres) i explotar les dades recollides a la base de dades. Cada espai tindria la seva lògica de funcionament automàtic específic. Entre les conclusions més rellevants obtingudes en aquest treball s’observa: · Que és pot reduir la potència contractada a la factura a l’estar per sota de la realment consumida. · Que no hi ha penalitzacions a la factura per consum de reactiva, ja que el compensador funciona correctament. · Que es pot reduir l’horari de l’inici del consum d’energia, ja que no correspon a l’activitat docent. · Els valors de la tensió i freqüència estan dintre de la normalitat. · Els harmònics estan al llindar màxim. Analitzant aquestes conclusions, voldria destacar les mesures correctores més importants que es poden dur a terme: canvi tecnològic a LED, temporitzar automàticament l’encesa i apagada dels fluorescents i equips informàtics de les aules “seguint calendari docent”, instal·lar sensors de moviment amb detecció lumínica als passadissos. Totes les conclusions extretes d’aquest treball, es poden aplicar a tots els edificis de la facultat, prèviament realitzant l’estudi individual de cadascuna, seguint els mateixos criteris per tal d’optimitzar la inversió.