Blocking Effects of Human Tau on Squid Giant Synapse Transmission and Its Prevention by T-817 MA

Filamentous tau inclusions are hallmarks of Alzheimer's disease and related neurodegenerative tauopathies, but the molecular mechanisms involved in tau-mediated changes in neuronal function and their possible effects on synaptic transmission are unknown. We have evaluated the effects of human tau protein injected directly into the presynaptic terminal axon of the squid giant synapse, which affords functional, structural, and biochemical analysis of its action on the synaptic release process. Indeed, we have found that at physiological concentration recombinant human tau (h-tau42) becomes phosphorylated, produces a rapid synaptic transmission block, and induces the formation of clusters of aggregated synaptic vesicles in the vicinity of the active zone. Presynaptic voltage clamp recordings demonstrate that h-tau42 does not modify the presynaptic calcium current amplitude or kinetics. Analysis of synaptic noise at the post-synaptic axon following presynaptic h-tau42 microinjection revealed an initial phase of increase spontaneous transmitter release followed by a marked reduction in noise. Finally, systemic administration of T-817MA, a proposed neuro-protective agent, rescued tau-induced synaptic abnormalities. Our results show novel mechanisms of h-tau42 mediated synaptic transmission failure and identify a potential therapeutic agent to treat tau-related neurotoxicity

Blocking Effects of Human Tau on Squid Giant Synapse Transmission and Its Prevention by T-817 MA

Filamentous tau inclusions are hallmarks of Alzheimer’s disease and related neurodegenerative tauopathies, but the molecular mechanisms involved in tau-mediated changes in neuronal function and their possible effects on synaptic transmission are unknown. We have evaluated the effects of human tau protein injected directly into the presynaptic terminal axon of the squid giant synapse, which affords functional, structural, and biochemical analysis of its action on the synaptic release process. Indeed, we have found that at physiological concentration recombinant human tau (h-tau42) becomes phosphorylated, produces a rapid synaptic transmission block, and induces the formation of clusters of aggregated synaptic vesicles in the vicinity of the active zone. Presynaptic voltage clamp recordings demonstrate that h-tau42 does not modify the presynaptic calcium current amplitude or kinetics. Analysis of synaptic noise at the post-synaptic axon following presynaptic h-tau42 microinjection revealed an initial phase of increase spontaneous transmitter release followed by a marked reduction in noise. Finally, systemic administration of T-817MA, a proposed neuro-protective agent, rescued tau-induced synaptic abnormalities. Our results show novel mechanisms of h-tau42 mediated synaptic transmission failure and identify a potential therapeutic agent to treat tau-related neurotoxicityGrant sponsors: NIH AG027476 to Herman Moreno; NS13742/ NS/NINDS/NIH HHS to RLl; FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo, Brasil) projects 2009/01571-6 and CinAPSe 05/56447-7 to Jorge E. Moreira.Peer Reviewe

The Relationship between Self-City Brand Connection, City Brand Experience, and City Brand Ambassadors

The city brand experience of residents has emerged as an important topic due to the concentration of the city population and changes in the marketing environment. This study examined the relationship between self-city brand connection, city brand experience, city brand satisfaction, and city brand ambassadorship behavior intention (CBABI) in city residents. An empirical analysis was conducted using data collected through a questionnaire with 328 residents of Seoul and Busan in Korea. The results reveal that self-city brand connection is positively related to city brand experience and city brand satisfaction but is not directly related to CBABI. Next, city brand experience was found to have a significant positive relationship with city brand satisfaction and CBABI, and city brand satisfaction is positively related to CBABI. We also found differences in the effects of city brand satisfaction on CBABI between Seoul and Busan. Although city brand satisfaction had a significant effect on CBABI in both cities, the effect was greater in Busan. This study confirms the effect of citizens’ city brand experiences and identifies the path by which city residents become city brand ambassadors

Trouble-makers in cytologic interpretation of the uterine cervix

The development and standardization of cytologic screening of the uterine cervix has dramatically decreased the prevalence of squamous cell carcinoma of the uterine cervix. Advances in the understanding of biology of human papillomavirus have contributed to upgrading the histologic diagnosis of the uterine cervix; however, cytologic screening that should triage those that need further management still poses several difficulties in interpretation. Cytologic features of high grade intraepithelial squamous lesion (HSIL) mimics including atrophy, immature metaplasia, and transitional metaplasia, and glandular lesion masquerades including tubal metaplasia and HSIL with glandular involvement are described with accentuation mainly on the differential points. When the cytologic features lie in a gray zone between the differentials, the most important key to the more accurate interpretation is sticking to the very basics of cytology; screening the background and cellular architecture, and then scrutinizing the nuclear and cytoplasmic details

Antimicrobial Resistance in Haemophilus influenzae Respiratory Tract Isolates in Korea: Results of a Nationwide Acute Respiratory Infections Surveillance▿

Antimicrobial susceptibility patterns and β-lactam resistance mechanisms of 544 Haemophilus influenzae isolates through the nationwide Acute Respiratory Infections Surveillance (ARIS) network in Korea during 2005 and 2006 were determined. Resistance to ampicillin was 58.5%, followed by resistance to cefuroxime (23.3%), clarithromycin (18.7%), cefaclor (17.0%), amoxicillin-clavulanate (10.4%), and chloramphenicol (8.1%). Levofloxacin and cefotaxime were the most active agents tested in this study. β-Lactamase production (52.4%) was the main mechanism of ampicillin resistance, affecting 96.1% of TEM-1-type β-lactamase. According to their β-lactam resistance mechanisms, all isolates were classified into the following groups: β-lactamase-negative, ampicillin-sensitive (BLNAS) strains (n = 224; 41.5%); β-lactamase-positive, ampicillin-resistant (BLPAR) strains (n = 255; 47.2%); β-lactamase-negative, ampicillin-resistant (BLNAR) strains (n = 33; 6.1%); and β-lactamase-positive, amoxicillin-clavulanate-resistant (BLPACR) strains (n = 28; 5.2%). Among the BLNAR and BLPACR strains, there were various patterns of multiple-amino-acid substitutions in penicillin-binding protein 3. Particularly, among BLNAR, group III isolates, which had three simultaneous substitutions (Met377Ile, Ser385Thr, and Leu389Phe), were identified for the first time in Korea. Three group III strains displayed the highest MIC of cefotaxime (1 to 2 μg/ml). The results indicate the importance of monitoring a changing situation pertaining to the increase and spread of BLNAR and BLPACR strains of H. influenzae for appropriate antibiotic therapy for patients with respiratory tract infections in Korea

Subthreshold membrane potential oscillations in inferior olive neurons are dynamically regulated by P/Q- and T-type calcium channels: a study in mutant mice

The role of P/Q- and T-type calcium channels in the rhythmic oscillatory behaviour of inferior olive (IO) neurons was investigated in mutant mice. Mice lacking either the CaV2.1 gene of the pore-forming α1A subunit for P/Q-type calcium channel, or the CaV3.1 gene of the pore-forming α1G subunit for T-type calcium channel were used. In vitro intracellular recording from IO neurons reveals that the amplitude and frequency of sinusoidal subthreshold oscillations (SSTOs) were reduced in the CaV2.1−/− mice. In the CaV3.1−/− mice, IO neurons also showed altered patterns of SSTOs and the probability of SSTO generation was significantly lower (15%, 5 of 34 neurons) than that of wild-type (78%, 31 of 40 neurons) or CaV2.1−/− mice (73%, 22 of 30 neurons). In addition, the low-threshold calcium spike and the sustained endogenous oscillation following rebound potentials were absent in IO neurons from CaV3.1−/− mice. Moreover, the phase-reset dynamics of oscillatory properties of single neurons and neuronal clusters in IO were remarkably altered in both CaV2.1−/− and CaV3.1−/− mice. These results suggest that both α1A P/Q- and α1G T-type calcium channels are required for the dynamic control of neuronal oscillations in the IO. These findings were supported by results from a mathematical IO neuronal model that incorporated T and P/Q channel kinetics

Upconversion-Triggered Charge Separation in Polymer Semiconductors

Upconversion is a unique optical property which is driven by a sequential photon pumping and generation of higher energy photons in a consecutive manner. The efficiency improvement in photovoltaic devices can be achieved when upconverters are integrated since upconverters contribute to the generation of extra photons. Despite numerous experimental studies confirming the relationship, fundamental explanations for a real contribution of upconversion to photovoltaic efficiency are still in demand. In this respect, we suggest a new approach to visualize the upconversion event in terms of surface photovoltage (SPV) by virtue of Kelvin probe force microscopy (KPFM). One of the most conventional polymer semiconductors, poly(3-hexyl thiophene) (P3HT), is employed as a sensitizer to generate charge carriers by upconverted light. KPFM measurements reveal that the light upconversion enabled the formation of charge carriers in P3HT, resulting in large SPV of -54.9 mV. It confirms that the energy transfer from upconverters to P3HT can positively impact on the device performance in organic solar cells (OSCs).clos