Impaired osteoblast differentiation in annexin A2- and -A5-deficient cells.

Annexins are a class of calcium-binding proteins with diverse functions in the regulation of lipid rafts, inflammation, fibrinolysis, transcriptional programming and ion transport. Within bone, they are well-characterized as components of mineralizing matrix vesicles, although little else is known as to their function during osteogenesis. We employed shRNA to generate annexin A2 (AnxA2)- or annexin A5 (AnxA5)-knockdown pre-osteoblasts, and determined whether proliferation or osteogenic differentiation was altered in knockdown cells, compared to pSiren (Si) controls. We report that DNA content, a marker of proliferation, was significantly reduced in both AnxA2 and AnxA5 knockdown cells. Alkaline phosphatase expression and activity were also suppressed in AnxA2- or AnxA5-knockdown after 14 days of culture. The pattern of osteogenic gene expression was altered in knockdown cells, with Col1a1 expressed more rapidly in knock-down cells, compared to pSiren. In contrast, Runx2, Ibsp, and Bglap all revealed decreased expression after 14 days of culture. In both AnxA2- and AnxA5-knockdown, interleukin-induced STAT6 signaling was markedly attenuated compared to pSiren controls. These data suggest that AnxA2 and AnxA5 can influence bone formation via regulation of osteoprogenitor proliferation, differentiation, and responsiveness to cytokines in addition to their well-studied function in matrix vesicles

Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin

Loss of E-cadherin expression or function in tumors leads to a more invasive phenotype. In this study, we investigated whether the invasion suppressor activity of E-cadherin is mediated directly by tighter physical cell adhesion, indirectly by sequestering β-catenin and thus antagonizing β-catenin/T cell factor (TCF) signaling, or by other signaling pathways. To distinguish mechanisms, we expressed wild-type E-cadherin and various E-cadherin mutants in invasive E-cadherin–negative human breast (MDA-MB-231) and prostate (TSU-Pr1) epithelial carcinoma cell lines using a tetracycline-inducible system. Our data confirm that E-cadherin inhibits human mammary and prostate tumor cell invasion. We find that adhesion is neither necessary nor sufficient for suppressing cancer invasion. Rather, the invasion suppressor signal is mediated through the β-catenin–binding domain of the E-cadherin cytoplasmic tail but not through the p120ctn-binding domain. β-catenin depletion also results in invasion suppression. However, alteration in the β-catenin/TCF transcriptional regulation of target genes is not required for the invasion suppressor activity of E-cadherin, suggesting the involvement of other β-catenin–binding proteins

Characterizing Human Random-Sequence Generation in Competitive and Non-Competitive Environments Using Lempel-Ziv Complexity

The human ability for random-sequence generation (RSG) is limited but improves in a competitive game environment with feedback. However, it remains unclear how random people can be during games and whether RSG during games can improve when explicitly informing people that they must be as random as possible to win the game. Nor is it known whether any such improvement in RSG transfers outside the game environment. To investigate this, we designed a pre/post intervention paradigm around a Rock-Paper-Scissors game followed by a questionnaire. During the game, we manipulated participants’ level of awareness of the computer’s strategy; they were either (a) not informed of the computer’s algorithm or (b) explicitly informed that the computer used patterns in their choice history against them, so they must be maximally random to win. Using a compressibility metric of randomness, our results demonstrate that human RSG can reach levels statistically indistinguishable from computer pseudo-random generators in a competitive-game setting. However, our results also suggest that human RSG cannot be further improved by explicitly informing participants that they need to be random to win. In addition, the higher RSG in the game setting does not transfer outside the game environment. Furthermore, we found that the underrepresentation of long repetitions of the same entry in the series explains up to 29% of the variability in human RSG, and we discuss what might make up the variance left unexplained

ILL in the faster lane: empowering users with HKALL

In an environment of reduced funding for higher education institutions, and consequently reduced funding for the libraries of those institutions, three of the eight university libraries in the Hong Kong Special Administrative Region of China (HKSAR) embarked on an ambitious trial. With a main objective to achieve greater value for money and greater quality of service in the use of their libraries’ shrinking budgets, the libraries at the University of Hong Kong, the City University of Hong Kong, and Lingnan University sought to assess the impact of the introduction of a collaborative, user-initiated, unmediated, interlibrary loan service. Following a period of examination and discussion, INNOVATIVE’s INN-Reach module was chosen as the preferred system to be used during the trial which commenced in January, 2004. In this paper, the authors will explore the reasons behind conducting such a trial, the issues that confronted the collaborating partners before and during the trial, as well as an assessment of the degree of success of the project. In particular, following the trial period of nine months, the three university libraries sought answers to a number of important questions. Through a detailed analysis of available data, coupled with user and library staff evaluation obtained through surveys and focus groups, these questions were answered. In their paper the authors will outline the answers to these questions along with other lessons learned. The paper will conclude with a look to the future for collaborative, user-initiated, unmediated, interlibrary loan services in Hong Kong.published_or_final_version9th Interlending and Document Supply International Conferenc

Pharmacology of ginsenosides: a literature review

The therapeutic potential of ginseng has been studied extensively, and ginsenosides, the active components of ginseng, are shown to be involved in modulating multiple physiological activities. This article will review the structure, systemic transformation and bioavailability of ginsenosides before illustration on how these molecules exert their functions via interactions with steroidal receptors. The multiple biological actions make ginsenosides as important resources for developing new modalities. Yet, low bioavailability of ginsenoside is one of the major hurdles needs to be overcome to advance its use in clinical settings

Modulation of Synaptic Plasticity by Stress Hormone Associates with Plastic Alteration of Synaptic NMDA Receptor in the Adult Hippocampus

Stress exerts a profound impact on learning and memory, in part, through the actions of adrenal corticosterone (CORT) on synaptic plasticity, a cellular model of learning and memory. Increasing findings suggest that CORT exerts its impact on synaptic plasticity by altering the functional properties of glutamate receptors, which include changes in the motility and function of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptor (AMPAR) that are responsible for the expression of synaptic plasticity. Here we provide evidence that CORT could also regulate synaptic plasticity by modulating the function of synaptic N-methyl-D-aspartate receptors (NMDARs), which mediate the induction of synaptic plasticity. We found that stress level CORT applied to adult rat hippocampal slices potentiated evoked NMDAR-mediated synaptic responses within 30 min. Surprisingly, following this fast-onset change, we observed a slow-onset (>1 hour after termination of CORT exposure) increase in synaptic expression of GluN2A-containing NMDARs. To investigate the consequences of the distinct fast- and slow-onset modulation of NMDARs for synaptic plasticity, we examined the formation of long-term potentiation (LTP) and long-term depression (LTD) within relevant time windows. Paralleling the increased NMDAR function, both LTP and LTD were facilitated during CORT treatment. However, 1–2 hours after CORT treatment when synaptic expression of GluN2A-containing NMDARs is increased, bidirectional plasticity was no longer facilitated. Our findings reveal the remarkable plasticity of NMDARs in the adult hippocampus in response to CORT. CORT-mediated slow-onset increase in GluN2A in hippocampal synapses could be a homeostatic mechanism to normalize synaptic plasticity following fast-onset stress-induced facilitation

Early affective changes and increased connectivity in preclinical Alzheimer's disease.

IntroductionAffective changes precede cognitive decline in mild Alzheimer's disease and may relate to increased connectivity in a "salience network" attuned to emotionally significant stimuli. The trajectory of affective changes in preclinical Alzheimer's disease, and its relationship to this network, is unknown.MethodsOne hundred one cognitively normal older adults received longitudinal assessments of affective symptoms, then amyloid-PET. We hypothesized amyloid-positive individuals would show enhanced emotional reactivity associated with salience network connectivity. We tested whether increased global connectivity in key regions significantly related to affective changes.ResultsIn participants later found to be amyloid positive, emotional reactivity increased with age, and interpersonal warmth declined in women. These individuals showed higher global connectivity within the right insula and superior temporal sulcus; higher superior temporal sulcus connectivity predicted increasing emotional reactivity and decreasing interpersonal warmth.ConclusionsAffective changes should be considered an early preclinical feature of Alzheimer's disease. These changes may relate to higher functional connectivity in regions critical for social-emotional processing