Direct modulation of electroluminescence from silicon nanocrystals beyond radiative recombination rates

We propose a light emitting transistor based on silicon nanocrystals provided with 200 Mbits/ s built-in modulation. Suppression of electroluminescence from silicon nanocrystals embedded into the gate oxide of a field effect transistor is achieved by fast Auger quenching. In this process, a modulating drain signal causes heating of carriers in the channel and facilitates the charge injection into the nanocrystals. This excess of charge enables fast nonradiative processes that are used to obtain 100% modulation depths at modulating voltages of 1 V.

Direct modulation of calmodulin targets by the neuronal calcium sensor NCS-1.

Ca2+ and its ubiquitous intracellular receptor calmodulin (CaM) are required in the nervous system, among a host of cellular responses, for the modulation of several important enzymes and ion channels involved in synaptic efficacy and neuronal plasticity. Here, we report that CaM can be replaced by the neuronal calcium sensor NCS-1 both in vitro and in vivo. NCS-1 is a calcium binding protein with two Ca(2+)-binding domains that shares only 21% of homology with CaM. We observe that NCS-1 directly activates two Ca2+/CaM-dependent enzymes (3':5'-cyclic nucleotide phosphodiesterase and protein phosphatase calcineurin). Co-activation of nitric oxide synthase by NCS-1 and CaM results in a higher activity than with CaM alone. Moreover, NCS-1 is coexpressed with calcineurin and nitric oxide synthase in several neuron populations. Finally, injections of NCS-1 into calmodulin-defective cam1 Paramecium partially restore wildtype behavioral responses. With this highly purified preparation of NCS-1, we have obtained crystals suitable for crystallographic structure studies. NCS-1, despite its very different structure, distribution, and Ca(2+)-binding affinity as compared with CaM, can substitute for or potentiate CaM functions. Therefore, NCS-1 represents a novel protein capable of mediating multiple Ca(2+)-signaling pathways in the nervous system.

Cost-efficient OFDM generation at 60-GHz by heterodyne technique with direct modulation and envelope detector

A cost-effective radio over fiber system to up-convert and transmit multigigabit signals at 60 GHz is presented. A low intermediate frequency OFDM signal is used to directly modulate a laser, which is combined with an independent unmodulated laser. The generated millimeter wave frequency can be adjusted by tuning the frequency separation between the lasers. Since no external modulator is required, this technique is low-cost and it is easily integrable in a single chip. In this paper, we present numerical results showing the feasibility of generating an IEEE 802.15.3c compliant 3.5-Gbps 60-GHz OFDM. We show that received signal quality is not limited by the lasers' linewidth but by the relative intensity noise. © 2013 IEEE.

The 22-Year Hale Cycle in cosmic ray flux: evidence for direct heliospheric modulation

The ability to predict times of greater galactic cosmic ray (GCR) fluxes is important for reducing the hazards caused by these particles to satellite communications, aviation, or astronauts. The 11-year solar-cycle variation in cosmic rays is highly correlated with the strength of the heliospheric magnetic field. Differences in GCR flux during alternate solar cycles yield a 22-year cycle, known as the Hale Cycle, which is thought to be due to different particle drift patterns when the northern solar pole has predominantly positive (denoted as qA>0 cycle) or negative (qA<0) polarities. This results in the onset of the peak cosmic-ray flux at Earth occurring earlier during qA>0 cycles than for qA<0 cycles, which in turn causes the peak to be more dome-shaped for qA>0 and more sharply peaked for qA<0. In this study, we demonstrate that properties of the large-scale heliospheric magnetic field are different during the declining phase of the qA<0 and qA>0 solar cycles, when the difference in GCR flux is most apparent. This suggests that particle drifts may not be the sole mechanism responsible for the Hale Cycle in GCR flux at Earth. However, we also demonstrate that these polarity-dependent heliospheric differences are evident during the space-age but are much less clear in earlier data: using geomagnetic reconstructions, we show that for the period of 1905 - 1965, alternate polarities do not give as significant a difference during the declining phase of the solar cycle. Thus we suggest that the 22-year cycle in cosmic-ray flux is at least partly the result of direct modulation by the heliospheric magnetic field and that this effect may be primarily limited to the grand solar maximum of the space-age.

Direct adipotropic actions of atorvastatin: differentiation state-dependent induction of apoptosis, modulation of endocrine function, and inhibition of glucose uptake

Statins exert anti-inflammatory, anti-atherogenic actions. The mechanisms responsible for these effects remain only partially elucidated. Diabetes and obesity are characterized by low-grade inflammation. Metabolic and endocrine adipocyte dysfunction is known to play a crucial role in the development of these disorders and the related cardiovascular complications. Thus, direct modulation of adipocyte function may represent a mechanism of pleiotropic statin actions. We investigated effects of atorvastatin on apoptosis, differentiation, endocrine, and metabolic functions in murine white and brown adipocyte lines. Direct exposure of differentiating preadipocytes to atorvastatin strongly reduced lipid accumulation and diminished protein expression of the differentiation marker CCAAT/enhancer binding protein-beta (CEBP-beta). In fully differentiated adipocytes, however, lipid accumulation remained unchanged after chronic atorvastatin treatment. Furthermore, cell viability was reduced in response to atorvastatin treatment in proliferating and differentiating preadipocytes, but not in differentiated cells. Moreover, atorvastatin induced apoptosis and inhibited protein kinase B (AKT) phosphorylation in proliferating and differentiating preadipocytes, but not in differentiated adipocytes. On the endocrine level, direct atorvastatin treatment of differentiated white adipocytes enhanced expression of the pro-inflammatory adipokine interleukin-6 (IL-6), and downregulated expression of the insulin-mimetic and anti-inflammatory adipokines visfatin and adiponectin. Finally, these direct adipotropic endocrine effects of atorvastatin were paralleled by the acute inhibition of insulin-induced glucose uptake in differentiated white adipocytes, while protein expression of the thermogenic uncoupling protein-1 (UCP-1) in brown adipocytes remained unchanged. Taken together, our data for the first time demonstrate direct differentiation state-dependent effects of atorvastatin including apoptosis, modulation of pro-inflammatory and glucostatic adipokine expression, and insulin resistance in adipose cells. These differential interactions may explain variable clinical observations.

Direct femtosecond laser inscription in transparent dielectrics

Since 1996 direct femtosecond inscription in transparent dielectrics has become the subject of intensive research. This enabling technology significantly expands the technological boundaries for direct fabrication of 3D structures in a wide variety of materials. It allows modification of non-photosensitive materials, which opens the door to numerous practical applications. In this work we explored the direct femtosecond inscription of waveguides and demonstrated at least one order of magnitude enhancement in the most critical parameter - the induced contrast of the refractive index in a standard borosilicate optical glass. A record high induced refractive contrast of 2.5×10-2 is demonstrated. The waveguides fabricated possess one of the lowest losses, approaching level of Fresnel reflection losses at the glassair interface. High refractive index contrast allows the fabrication of curvilinear waveguides with low bend losses. We also demonstrated the optimisation of the inscription regimes in BK7 glass over a broad range of experimental parameters and observed a counter-intuitive increase of the induced refractive index contrast with increasing translation speed of a sample. Examples of inscription in a number of transparent dielectrics hosts using high repetition rate fs laser system (both glasses and crystals) are also presented. Sub-wavelength scale periodic inscription inside any material often demands supercritical propagation regimes, when pulse peak power is more than the critical power for selffocusing, sometimes several times higher than the critical power. For a sub-critical regime, when the pulse peak power is less than the critical power for self-focusing, we derive analytic expressions for Gaussian beam focusing in the presence of Kerr non-linearity as well as for a number of other beam shapes commonly used in experiments, including astigmatic and ring-shaped ones. In the part devoted to the fabrication of periodic structures, we report on recent development of our point-by-point method, demonstrating the shortest periodic perturbation created in the bulk of a pure fused silica sample, by using third harmonics (? =267 nm) of fundamental laser frequency (? =800 nm) and 1 kHz femtosecond laser system. To overcome the fundamental limitations of the point-by-point method we suggested and experimentally demonstrated the micro-holographic inscription method, which is based on using the combination of a diffractive optical element and standard micro-objectives. Sub-500 nm periodic structures with a much higher aspect ratio were demonstrated. From the applications point of view, we demonstrate examples of photonics devices by direct femtosecond fabrication method, including various vectorial bend-sensors fabricated in standard optical fibres, as well as a highly birefringent long-period gratings by direct modulation method. To address the intrinsic limitations of femtosecond inscription at very shallow depths we suggested the hybrid mask-less lithography method. The method is based on precision ablation of a thin metal layer deposited on the surface of the sample to create a mask. After that an ion-exchange process in the melt of Ag-containing salts allows quick and low-cost fabrication of shallow waveguides and other components of integrated optics. This approach covers the gap in direct fs inscription of shallow waveguide. Perspectives and future developments of direct femtosecond micro-fabrication are also discussed.

Estudo comparativo entre sistemas RoF com modulação directa e com modulação externa

O RoF (Radio over Fiber) é uma tecnologia que permite a transmissão de sinais rádio de elevada largura de banda, fornecida pela fibra óptica, e simultaneamente mantêm a característica de mobilidade das redes de comunicação móvel. Esta dissertação de mestrado tem como objectivo estudar, simular e comparar sistemas RoF com modulação directa e com modulação externa, utilizando um sinal WiMAX, por ser uma tecnologia recente e com potencial de utilização futura. Desta forma foram avaliados três tipos de moduladores externos, sendo que o modulador EA (Electro-Absorption) é o que permite obter melhores valores de EVM e de SNR devido ao facto deste ter menores perdas de inserção na fibra. Da comparação entre o esquema com modulação directa e o esquema com modulação externa, é possível concluir que para larguras de banda mais baixas a utilização de modulação directa é mais eficiente que a modulação externa, mas à medida que a largura de banda aumenta a modulação externa apresenta claramente melhor desempenho. Isto deve-se ao facto de a modulação directa produzir mais chirp que a modulação externa, sendo que o chirp limita a largura de banda e o comprimento da fibra. De forma a melhorar o desempenho do sistema com modulação directa foi introduzido uma fibra com compensação de dispersão. Foi possível concluir que a utilização de fibra com compensação de dispersão é uma boa solução quando se pretende transmitir sinais de elevada largura de banda em esquemas com modulação directa.

The anabolic androgenic steroid fluoxymesterone inhibits 11β-hydroxysteroid dehydrogenase 2-dependent glucocorticoid inactivation.

Anabolic androgenic steroids (AAS) are testosterone derivatives used either clinically, in elite sports, or for body shaping with the goal to increase muscle size and strength. Clinically developed compounds and nonclinically tested designer steroids often marketed as food supplements are widely used. Despite the considerable evidence for various adverse effects of AAS use, the underlying molecular mechanisms are insufficiently understood. Here, we investigated whether some AAS, as a result of a lack of target selectivity, might inhibit 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2)-dependent inactivation of glucocorticoids. Using recombinant human 11β-HSD2, we observed inhibitory effects for several AAS. Whereas oxymetholone, oxymesterone, danazol, and testosterone showed medium inhibitory potential, fluoxymesterone was a potent inhibitor of human 11β-HSD2 (half-maximal inhibitory concentration [IC(50)] of 60-100nM in cell lysates; IC(50) of 160nM in intact SW-620, and 530nM in MCF-7 cells). Measurements with rat kidney microsomes and lysates of cells expressing recombinant mouse 11β-HSD2 revealed much weaker inhibition by the AAS tested, indicating that the adverse effects of AAS-dependent 11β-HSD2 inhibition cannot be investigated in rats and mice. Furthermore, we provide evidence that fluoxymesterone is metabolized to 11-oxofluoxymesterone by human 11β-HSD2. Structural modeling revealed similar binding modes for fluoxymesterone and cortisol, supporting a competitive mode of inhibition of 11β-HSD2-dependent cortisol oxidation by this AAS. No direct modulation of mineralocorticoid receptor (MR) function was observed. Thus, 11β-HSD2 inhibition by fluoxymesterone may cause cortisol-induced MR activation, thereby leading to electrolyte disturbances and contributing to the development of hypertension and cardiovascular disease.

Mécanismes cellulaires de l'induction du facteur de transcription Nur77 après un traitement aux antipsychotiques

Les antipsychotiques sont utilisés en clinique depuis plus de 50 ans pour pallier aux symptômes de la schizophrénie. Malgré une recherche intensive, les mécanismes cellulaires et moléculaires responsables de l’effet clinique de cette médication demeurent encore nébuleux. Ces drogues sont reconnues comme des antagonistes des récepteurs D2 de la dopamine et peuvent moduler la transcription génique dans le striatum. Au cours des recherches qui ont mené à l'écriture de cette thèse, nous avons exploré l’expression de Nur77, un facteur de transcription de la famille des récepteurs nucléaires, afin de caractériser le rôle de la dopamine, la sérotonine, l’adénosine et le glutamate dans la régulation génique contrôlée par les antagonistes D2. En premier lieu, nous avons examiné l’impact de la co-administration d’agents sérotonergiques et adrénergiques sur l’expression de l’ARNm de Nur77 induite par l’halopéridol, un antipsychotique de première génération. Nous avons observé que le 8-OH-DPAT et le MDL11939 préviennent partiellement l’induction de Nur77 dans le striatum. Au contraire, l’idazoxan potentialise l’effet de l’halopéridol sur l’expression de Nur77 alors que le prazosin reste sans effet. Ces résultats démontrent que l’expression striatale de Nur77 induite par l’halopéridol peut être modulée à la baisse avec un agoniste 5-HT1A ou un antagoniste 5-HT2A. Par la suite, nous avons évalué dans divers paradigmes expérimentaux l’effet de l’éticlopride, un antagoniste spécifique D2, afin d’explorer davantage le mécanisme de l’effet transcriptionnel des antagonistes D2. Étonnamment, la suppression de l’isoforme D2L chez la souris D2L KO ne réduit pas la réponse de l’éticlopride dans le striatum. Par contre, une lésion corticale avec l’acide iboténique bloque l’effet de l’éticlopride sur la transcription de Nur77, suggérant un rôle du glutamate. La combinaison d’un antagoniste des récepteurs métabotropes du glutamate de types 5 (mGluR5) et d’un antagoniste des récepteurs de l’adénosine A2A abolit complètement l’augmentation de la transcription de Nur77 induit par l’éticlopride dans le striatum. La modulation directe de l’expression striatale de Nur77 par les récepteurs mGluR5 et A2A a été confirmée dans un modèle de cultures organotypiques de tranches cérébrales. Ces résultats démontrent clairement que la modulation de l’expression génique dans le striatum, à la suite d’un traitement avec un antagoniste D2 pourrait être indépendante d’une interaction directe avec les récepteurs D2 post-synaptiques, et reposerait plutôt sur son interaction avec les récepteurs D2 hétérosynaptiques des afférences corticostriées et l’activation subséquente des récepteurs post-synaptiques du glutamate et de l’adénosine. En résumé, nos résultats suggèrent que l’interaction des antipsychotiques atypiques avec les récepteurs 5-HT2A et 5-HT1A pourrait expliquer la différence dans le patron d’expression génique induit par ces drogues en comparaison avec les antipsychotiques typiques. De plus, nos résultats révèlent un nouveau mécanisme d’action des antagonistes D2 et supportent un rôle primordial du glutamate et de l’adénosine dans les effets des antipsychotiques de première génération.

Nonlinear Dynamics of Semiconductor LasersControl and Synchronization of Chaos:

Nonlinear dynamics of laser systems has become an interesting area of research in recent times. Lasers are good examples of nonlinear dissipative systems showing many kinds of nonlinear phenomena such as chaos, multistability and quasiperiodicity. The study of these phenomena in lasers has fundamental scientific importance since the investigations on these effects reveal many interesting features of nonlinear effects in practical systems. Further, the understanding of the instabilities in lasers is helpful in detecting and controlling such effects. Chaos is one of the most interesting phenomena shown by nonlinear deterministic systems. It is found that, like many nonlinear dissipative systems, lasers also show chaos for certain ranges of parameters. Many investigations on laser chaos have been done in the last two decades. The earlier studies in this field were concentrated on the dynamical aspects of laser chaos. However, recent developments in this area mainly belong to the control and synchronization of chaos. A number of attempts have been reported in controlling or suppressing chaos in lasers since lasers are the practical systems aimed to operated in stable or periodic mode. On the other hand, laser chaos has been found to be applicable in high speed secure communication based on synchronization of chaos. Thus, chaos in laser systems has technological importance also. Semiconductor lasers are most applicable in the fields of optical communications among various kinds of laser due to many reasons such as their compactness, reliability modest cost and the opportunity of direct current modulation. They show chaos and other instabilities under various physical conditions such as direct modulation and optical or optoelectronic feedback. It is desirable for semiconductor lasers to have stable and regular operation. Thus, the understanding of chaos and other instabilities in semiconductor lasers and their xi control is highly important in photonics. We address the problem of controlling chaos produced by direct modulation of laser diodes. We consider the delay feedback control methods for this purpose and study their performance using numerical simulation. Besides the control of chaos, control of other nonlinear effects such as quasiperiodicity and bistability using delay feedback methods are also investigated. A number of secure communication schemes based on synchronization of chaos semiconductor lasers have been successfully demonstrated theoretically and experimentally. The current investigations in these field include the study of practical issues on the implementations of such encryption schemes. We theoretically study the issues such as channel delay, phase mismatch and frequency detuning on the synchronization of chaos in directly modulated laser diodes. It would be helpful for designing and implementing chaotic encryption schemes using synchronization of chaos in modulated semiconductor laser

Nonlinear Dynamics of Multiple Quantum Well Lasers: Chaos and Multistability

This thesis presents analytical and numerical results from studies based on the multiple quantum well laser rate equation model. We address the problem of controlling chaos produced by direct modulation of laser diodes. We consider the delay feedback control methods for this purpose and study their performance using numerical simulation. Besides the control of chaos, control of other nonlinear effects such as quasiperiodicity and bistability using delay feedback methods are also investigated.A number of secure communication schemes based on synchronization of chaos semiconductor lasers have been successfully demonstrated theoretically and experimentally. The current investigations in these field include the study of practical issues on the implementations of such encryption schemes. We theoretically study the issues such as channel delay, phase mismatch and frequency detuning on the synchronization of chaos in directly modulated laser diodes. It would be helpful for designing and implementing chaotic encryption schemes using synchronization of chaos in modulated semiconductor lasers.

Insulin and TOR pathways regulate cellular and organismal growth through the myc oncogene in Drosophila

A large body of literature documents in both mice and Drosophila the involvement of Insulin pathway in growth regulation, probably due to its role in glucose and lipid import, nutrient storage, and translation of RNAs implicated in ribosome biogenesis (Vanhaesebroeck et al. 2001). Moreover several lines of evidence implicate this pathway as a causal factor in cancer (Sale, 2008; Zeng and Yee 2007; Hursting et al., 2007; Chan et al., 2008). With regards to Myc, studies in cell culture have implied this family of transcription factors as regulators of the cell cycle that are rapidly induced in response to growth factors. Myc is a potent oncogene, rearranged and overexpressed in a wide range of human tumors and necessary during development. Its conditional knock-out in mice results in reduction of body weight due to defect in cell proliferation (Trumpp et al. 2001). Evidence from in vivo studies in Drosophila and mammals suggests a critical function for myc in cell growth regulation (Iritani and Eisenman 1999; Johnston et al. 1999; Kim et al. 2000; de Alboran et al. 2001; Douglas et al. 2001). This role is supported by our analysis of Myc target genes in Drosophila, which include genes involved in RNA binding, processing, ribosome biogenesis and nucleolar function (Orain et al 2003, Bellosta et al., 2005, Hulf et al, 2005). The fact that Insulin signaling and Myc have both been associated with growth control suggests that they may interact with each other. However, genetic evidence suggesting that Insulin signaling regulates Myc in vivo is lacking. In this work we were able to show, for the first time, a direct modulation of dMyc in response to Insulin stimulation/silencing both in vitro and in vivo. Our results suggest that dMyc up-regulation in response to DILPs signaling occurs both at the mRNA and potein level. We believe dMyc protein accumulation after Insulin signaling activation is conditioned to AKT-dependent GSK3β/sgg inactivation. In fact, we were able to demonstate that dMyc protein stabilization through phosphorylation is a conserved feature between Drosophila and vertebrates and requires multiple events. The final phosphorylation step, that results in a non-stable form of dMyc protein, ready to be degraded by the proteasome, is performed by GSK3β/sgg kinase (Sears, 2004). At the same time we demonstrated that CKI family of protein kinase are required to prime dMyc phosphorylation. DILPs and TOR/Nutrient signalings are known to communicate at several levels (Neufeld, 2003). For this reason we further investigated TOR contribution to dMyc-dependent growth regulation. dMyc protein accumulates in S2 cells after aminoacid stimulation, while its mRNA does not seem to be affected upon TORC1 inhibition, suggesting that the Nutrient pathway regulates dMyc mostly post-transcriptionally. In support to this hypothesis, we observed a TORC1-dependent GSK3β/sgg inactivation, further confirming a synergic effect of DILPs and Nutrients on dMyc protein stability. On the other hand, our data show that Rheb but not S6K, both downstream of the TOR kinase, contributes to the dMyc-induced growth of the eye tissue, suggesting that Rheb controls growth independently of S6K.. Moreover, Rheb seems to be able to regulate organ size during development inducing cell death, a mechanism no longer occurring in absence of dmyc. These observations suggest that Rheb might control growth through a new pathway independent of TOR/S6K but still dependent on dMyc. In order to dissect the mechanism of dMyc regulation in response to these events, we analyzed the relative contribution of Rheb, TOR and S6K to dMyc expression, biochemically in S2 cells and in vivo in morphogenetic clones and we further confirmed an interplay between Rheb and Myc that seems to be indipendent from TOR. In this work we clarified the mechanisms that stabilize dMyc protein in vitro and in vivo and we observed for the first time dMyc responsiveness to DILPs and TOR. At the same time, we discovered a new branch of the Nutrient pathway that appears to drive growth through dMyc but indipendently from TOR. We believe our work shed light on the mechanisms cells use to grow or restrain growth in presence/absence of growth promoting cues and for this reason it contributes to understand the physiology of growth control.

Gamma-secretase modulators and inhibitors in Alzheimer's disease: influence of genetic background on efficacy and mechanism of action

According to the amyloid hypothesis, Alzheimer’s disease (AD) is caused by aberrant production or clearance of the amyloid-β (Aβ) peptides, and in particular of the longer more aggregation-prone Aβ42. The Aβ peptides are generated through successive proteolytic cleavage of the amyloid precursor protein (APP) by the β-site APP cleaving enzyme (BACE) and γ-secretase. γ-secretase produces Aβ peptides with variable C-termini ranging from Aβ34 to Aβ48, presumably by sequential trimming of longer into shorter peptides. γ-secretase is a multiprotein complex consisting of at least four different proteins and the presenilin proteins (PS1 or PS2) contain the catalytic center of the complex. In 2001 several non-steroidal anti-inflammatory drugs were identified as the founding members of a new class of γ-secretase modulators (GSMs) that can selectively reduce production of Aβ42. Concomitantly, these GSMs increase Aβ38 production indicating closely coordinated generation of Aβ42 and Aβ38 and a potential precursor-product relationship between these peptides. GSMs seem to exert their activity by direct modulation of γ-secretase. Support for this hypothesis is drawn from the finding that some PS mutations associated with early-onset familial AD (FAD) can modulate the cellular response to GSMs and to γ-secretase inhibitors (GSIs), which inhibit production of all Aβ peptides and are known to directly interact with PS. A particularly interesting FAD PS mutation is PS1-ΔExon9, a complex deletion mutant that blocks endoproteolysis of PS1 and renders cells completely non-responsive to GSMs. Studies presented in this thesis show that the diminished response of PS1-ΔExon9 to GSMs is mainly caused by its lack of endoproteolytic cleavage. Furthermore, we were able to demonstrate that a reduced response to GSMs and GSIs is not limited to PS1-ΔExon9 but is a common effect of aggressive FAD-associated PS1 mutations. Surprisingly, we also found that while the Aβ42 response to GSMs is almost completely abolished by these PS1 mutations, the accompanying Aβ38 increase was indistinguishable to wild-type PS1. Finally, the reduced response to GSIs was confirmed in a mouse model with transgenic expression of an aggressive FAD-associated PS1 mutation as a highly potent GSI failed to reduce Aβ42 levels in brain of these mice. Taken together, our findings provide clear evidence for independent generation of Aβ42 and Aβ38 peptides, and argue that the sequential cleavage model might be an oversimplification of the molecular mechanism of γ-secretase. Most importantly, our results highlight the significance of genetic background in drug discovery efforts aimed at γ-secretase, and indicate that the use of cellular models with transgenic expression of FAD-associated PS mutations might confound studies of the potency and efficacy of GSMs and GSIs. Therefore, such models should be strictly avoided in the ongoing preclinical development of these promising and potentially disease-modifying therapeutics for AD.

More than synaptic plasticity: role of nonsynaptic plasticity in learning and memory.

Decades of research on the cellular mechanisms of memory have led to the widely held view that memories are stored as modifications of synaptic strength. These changes involve presynaptic processes, such as direct modulation of the release machinery, or postsynaptic processes, such as modulation of receptor properties. Parallel studies have revealed that memories might also be stored by nonsynaptic processes, such as modulation of voltage-dependent membrane conductances, which are expressed as changes in neuronal excitability. Although in some cases nonsynaptic changes can function as part of the engram itself, they might also serve as mechanisms through which a neural circuit is set to a permissive state to facilitate synaptic modifications that are necessary for memory storage.

The Salmonella pathogenicity island (SPI)-2 and SPI-1 type III secretion systems allow Salmonella serovar typhimurium to trigger colitis via MyD88-dependent and MyD88-independent mechanisms.

Salmonella typhimurium can colonize the gut, invade intestinal tissues, and cause enterocolitis. In vitro studies suggest different mechanisms leading to mucosal inflammation, including 1) direct modulation of proinflammatory signaling by bacterial type III effector proteins and 2) disruption or penetration of the intestinal epithelium so that penetrating bacteria or bacterial products can trigger innate immunity (i.e., TLR signaling). We studied these mechanisms in vivo using streptomycin-pretreated wild-type and knockout mice including MyD88(-/-) animals lacking an adaptor molecule required for signaling via most TLRs. The Salmonella SPI-1 and the SPI-2 type III secretion systems (TTSS) contributed to inflammation. Mutants that retain only a functional SPI-1 (M556; sseD::aphT) or a SPI-2 TTSS (SB161; DeltainvG) caused attenuated colitis, which reflected distinct aspects of the colitis caused by wild-type S. typhimurium: M556 caused diffuse cecal inflammation that did not require MyD88 signaling. In contrast, SB161 induced focal mucosal inflammation requiring MyD88. M556 but not SB161 was found in intestinal epithelial cells. In the lamina propria, M556 and SB161 appeared to reside in different leukocyte cell populations as indicated by differential CD11c staining. Only the SPI-2-dependent inflammatory pathway required aroA-dependent intracellular growth. Thus, S. typhimurium can use two independent mechanisms to elicit colitis in vivo: SPI-1-dependent and MyD88-independent signaling to epithelial cells and SPI-2-dependent intracellular proliferation in the lamina propria triggering MyD88-dependent innate immune responses.