Random subtrees of complete graphs

We study the asymptotic behavior of four statistics associated with subtrees of complete graphs: the uniform probability $p_n$ that a random subtree is a spanning tree of $K_n$, the weighted probability $q_n$ (where the probability a subtree is chosen is proportional to the number of edges in the subtree) that a random subtree spans and the two expectations associated with these two probabilities. We find $p_n$ and $q_n$ both approach $e^{-e^{-1}}\approx .692$, while both expectations approach the size of a spanning tree, i.e., a random subtree of $K_n$ has approximately $n-1$ edges

Reduction in Learning Rates Associated with Anterograde Interference Results from Interactions between Different Timescales in Motor Adaptation

Prior experiences can influence future actions. These experiences can not only drive adaptive changes in motor output, but they can also modulate the rate at which these adaptive changes occur. Here we studied anterograde interference in motor adaptation – the ability of a previously learned motor task (Task A) to reduce the rate of subsequently learning a different (and usually opposite) motor task (Task B). We examined the formation of the motor system's capacity for anterograde interference in the adaptive control of human reaching-arm movements by determining the amount of interference after varying durations of exposure to Task A (13, 41, 112, 230, and 369 trials). We found that the amount of anterograde interference observed in the learning of Task B increased with the duration of Task A. However, this increase did not continue indefinitely; instead, the interference reached asymptote after 15–40 trials of Task A. Interestingly, we found that a recently proposed multi-rate model of motor adaptation, composed of two distinct but interacting adaptive processes, predicts several key features of the interference patterns we observed. Specifically, this computational model (without any free parameters) predicts the initial growth and leveling off of anterograde interference that we describe, as well as the asymptotic amount of interference that we observe experimentally (R2 = 0.91). Understanding the mechanisms underlying anterograde interference in motor adaptation may enable the development of improved training and rehabilitation paradigms that mitigate unwanted interference.Engineering and Applied Science

The Relationship Of Development Status Of Investee Countries And Investor Perceptions Of Foreign Earnings

This study investigates the impact of corporate internationalization and the development status of investee countries on the foreign earnings response coefficient (FERC), which is a measure of the value-relevance of foreign earnings. To improve competitiveness, firms worldwide have expanded aggressively into foreign markets, thereby increasing their exposure to external risks and uncertainties on the one hand, and sources of growth and reward on the other. Using a Taiwanese sample, we found that greater corporate internationalization via investments in developed countries was positively related to the foreign ERC. We expected, and found, that companies can enhance the positive effects of internationalization by investing in countries that are relatively better developed than in countries that are less well developed. The public policy implications of these findings are discussed

NFAT promotes carcinoma invasive migration through glypican-6

Invasive migration of carcinoma cells is a prerequisite for the metastatic dissemination of solid tumours. Numerous mechanisms control the ability of cancer cells to acquire a motile and invasive phenotype, and subsequently degrade and invade the basement membrane. Several genes that are up-regulated in breast carcinoma are responsible for mediating the metastatic cascade. Recent studies have revealed that the NFAT (nuclear factor of activated T-cells) is a transcription factor that is highly expressed in aggressive breast cancer cells and tissues, and mediates invasion through transcriptional induction of pro-invasion and migration genes. In the present paper we demonstrate that NFAT promotes breast carcinoma invasion through induction of GPC (glypican) 6, a cell-surface glycoprotein. NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype. The mechanism by which GPC6 promotes invasive migration involves inhibition of canonical β-catenin and Wnt signalling, and up-regulation of non-canonical Wnt5A signalling leading to the activation of JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase). Thus GPC6 is a novel NFAT target gene in breast cancer cells that promotes invasive migration through Wnt5A signalling

Germline genetic variation and predicting immune checkpoint inhibitor induced toxicity

Immune checkpoint inhibitor (ICI) therapy has revolutionised the treatment of various cancer types. ICIs reinstate T-cell function to elicit an anti-cancer immune response. The resulting immune response can however have off-target effects which manifest as autoimmune type serious immune-related adverse events (irAE) in ~10–55% of patients treated. It is currently challenging to predict both who will experience irAEs and to what severity. Identification of patients at high risk of serious irAE would revolutionise patient care. While the pathogenesis driving irAE development is still unclear, host genetic factors are proposed to be key determinants of these events. This review presents current evidence supporting the role of the host genome in determining risk of irAE. We summarise the spectrum and timing of irAEs following treatment with ICIs and describe currently reported germline genetic variation associated with expression of immuno-modulatory factors within the cancer immunity cycle, development of autoimmune disease and irAE occurrence. We propose that germline genetic determinants of host immune function and autoimmune diseases could also explain risk of irAE development. We also endorse genome-wide association studies of patients being treated with ICIs to identify genetic variants that can be used in polygenic risk scores to predict risk of irAE

Membrane Transport Mechanisms Probed by Capacitance Measurements With Megahertz Voltage Clamp

We have used capacitance measurements with a 1-µs voltage clamp technique to probe electrogenic ion-transporter interactions in giant excised membrane patches, The hydrophobic ion dipicrylamine was used to test model predictions for a simple charge-moving reaction. The voltage and frequency dependencies of the apparent dipicrylamine-induced capacitance, monitored by 1-mV sinusoidal perturbations, correspond to single charges moving across 76% of the membrane field at a rate of 9500 s^(-1) at 0 mV. For the cardiac Na,K pump, the combined presence of cytoplasmic ATP-and sodium induces an increase of apparent membrane capacitance which requires the presence of extracellular sodium, The dependencies of capacitance changes on frequency, voltage, ATP, and sodium verify that phosphorylation enables a slow 300- to 900-s^(-1), pump transition (the E_1-E_2 conformational change), which in turn enables fast, electrogenic, extracellular sodium binding reactions, For the GAT1 (y-aminobutyric acid,Na,Cl) cotransporter, expressed in Xenopus oocyte membrane, we find that chloride binding from the cytoplasmic side, and probably sodium binding from the extracellular side, results in a decrease of membrane capacitance monitored with 1- to 50-kHz perturbation frequencies. Evidently, ion binding by the GAT1 transporter suppresses an intrinsic fast charge movement which mag originate from a mobility of charged residues of the transporter binding sites. The results demonstrate that fast capacitance measurements can provide new insight into electrogenic processes closely associated with ion binding by membrane transporters

Knockdown of the DNA repair and redox signaling protein Ape1/ Ref-1 blocks ovarian cancer cell and tumor growth

Apurinic endonuclease 1/redox effector factor-1 (Ape1/Ref-1 or Ape1) is an essential protein with two distinct functions. It is a DNA repair enzyme in the base excision repair (BER) pathway and a reduction–oxidation (redox) signaling factor maintaining transcription factors in an active reduced state. Our laboratory previously demonstrated that Ape1 is overexpressed in ovarian cancer and potentially contributes to resistance. Therefore, we utilized siRNA technology to knockdown protein levels of Ape1 in ovarian cancer cell line, SKOV-3x. Knocking Ape1 down had dramatic effects on cell growth in vitro but was not due to an increase in apoptosis and at least partially due to an extension in transit time through S-phase. Similarly, human ovarian tumor xenografts with reduced levels of Ape1 protein demonstrated a dramatic reduction in tumor volume (p < 0.01) and also statistically significant (p = 0.02) differences in 18F-fluorodeoxyglucose (FDG) uptake indicating reduced glucose metabolism and cellular proliferation. Ape1's role in DNA repair and redox signaling is important to our basic understanding of ovarian cancer cell growth and these findings strongly support Ape1 as a therapeutic target