Pharmacometabolomic mapping of early biochemical changes induced by sertraline and placebo.

In this study, we characterized early biochemical changes associated with sertraline and placebo administration and changes associated with a reduction in depressive symptoms in patients with major depressive disorder (MDD). MDD patients received sertraline or placebo in a double-blind 4-week trial; baseline, 1 week, and 4 weeks serum samples were profiled using a gas chromatography time of flight mass spectrometry metabolomics platform. Intermediates of TCA and urea cycles, fatty acids and intermediates of lipid biosynthesis, amino acids, sugars and gut-derived metabolites were changed after 1 and 4 weeks of treatment. Some of the changes were common to the sertraline- and placebo-treated groups. Changes after 4 weeks of treatment in both groups were more extensive. Pathway analysis in the sertraline group suggested an effect of drug on ABC and solute transporters, fatty acid receptors and transporters, G signaling molecules and regulation of lipid metabolism. Correlation between biochemical changes and treatment outcomes in the sertraline group suggested a strong association with changes in levels of branched chain amino acids (BCAAs), lower BCAAs levels correlated with better treatment outcomes; pathway analysis in this group revealed that methionine and tyrosine correlated with BCAAs. Lower levels of lactic acid, higher levels of TCA/urea cycle intermediates, and 3-hydroxybutanoic acid correlated with better treatment outcomes in placebo group. Results of this study indicate that biochemical changes induced by drug continue to evolve over 4 weeks of treatment and that might explain partially delayed response. Response to drug and response to placebo share common pathways but some pathways are more affected by drug treatment. BCAAs seem to be implicated in mechanisms of recovery from a depressed state following sertraline treatment

Humanising the mouse genome piece by piece

To better understand human health and disease, researchers create a wide variety of mouse models that carry human DNA. With recent advances in genome engineering, the targeted replacement of mouse genomic regions with orthologous human sequences has become increasingly viable, ranging from finely tuned humanisation of individual nucleotides and amino acids to the incorporation of many megabases of human DNA. Here, we examine emerging technologies for targeted genomic humanisation, we review the spectrum of existing genomically humanised mouse models and the insights such models have provided, and consider the lessons learned for designing such models in the future

Clades and clans: a comparison study of two evolutionary models

The Yule-Harding-Kingman (YHK) model and the proportional to distinguishable arrangements (PDA) model are two binary tree generating models that are widely used in evolutionary biology. Understanding the distributions of clade sizes under these two models provides valuable insights into macro-evolutionary processes, and is important in hypothesis testing and Bayesian analyses in phylogenetics. Here we show that these distributions are log-convex, which implies that very large clades or very small clades are more likely to occur under these two models. Moreover, we prove that there exists a critical value $\kappa(n)$ for each $n\geqslant 4$ such that for a given clade with size $k$, the probability that this clade is contained in a random tree with $n$ leaves generated under the YHK model is higher than that under the PDA model if $1<k<\kappa(n)$, and lower if $\kappa(n)<k<n$. Finally, we extend our results to binary unrooted trees, and obtain similar results for the distributions of clan sizes.Comment: 21page

The Drosophila Anion Exchanger (DAE) lacks a detectable interaction with the spectrin cytoskeleton

<p>Abstract</p> <p>Background</p> <p>Current models suggest that the spectrin cytoskeleton stabilizes interacting ion transport proteins at the plasma membrane. The human erythrocyte anion exchanger (AE1) was the first membrane transport protein found to be associated with the spectrin cytoskeleton. Here we evaluated a conserved anion exchanger from Drosophila (DAE) as a marker for studies of the downstream effects of spectrin cytoskeleton mutations.</p> <p>Results</p> <p>Sequence comparisons established that DAE belongs to the SLC4A1-3 subfamily of anion exchangers that includes human AE1. Striking sequence conservation was observed in the C-terminal membrane transport domain and parts of the N-terminal cytoplasmic domain, but not in the proposed ankyrin-binding site. Using an antibody raised against DAE and a recombinant transgene expressed in <it>Drosophila </it>S2 cells DAE was shown to be a 136 kd plasma membrane protein. A major site of expression was found in the stomach acid-secreting region of the larval midgut. DAE codistributed with an infolded subcompartment of the basal plasma membrane of interstitial cells. However, spectrin did not codistribute with DAE at this site or in anterior midgut cells that abundantly expressed both spectrin and DAE. Ubiquitous knockdown of DAE with dsRNA eliminated antibody staining and was lethal, indicating that DAE is an essential gene product in <it>Drosophila</it>.</p> <p>Conclusions</p> <p>Based on the lack of colocalization and the lack of sequence conservation at the ankyrin-binding site, it appears that the well-characterized interaction between AE1 and the spectrin cytoskeleton in erythrocytes is not conserved in <it>Drosophila</it>. The results establish a pattern in which most of the known interactions between the spectrin cytoskeleton and the plasma membrane in mammals do not appear to be conserved in <it>Drosophila</it>.</p

Early growth response gene-2 (Egr-2) regulates the development of B and T cells

The study was supported by Arthritis Research UK. Copyright @ 2011 Li et al.BACKGROUND: Understanding of how transcription factors are involved in lymphocyte development still remains a challenge. It has been shown that Egr-2 deficiency results in impaired NKT cell development and defective positive selection of T cells. Here we investigated the development of T, B and NKT cells in Egr-2 transgenic mice and the roles in the regulation of distinct stages of B and T cell development. METHODS AND FINDINGS: The expression of Egr1, 2 and 3 were analysed at different stages of T and B cell development by RT-PCT and results showed that the expression was strictly regulated at different stages. Forced expression of Egr-2 in CD2+ lymphocytes resulted in a severe reduction of CD4+CD8+ (DP) cells in thymus and pro-B cells in bone marrow, which was associated with reduced expression of Notch1 in ISP thymocytes and Pax5 in pro-B cells, suggesting that retraction of Egr-2 at the ISP and pro-B cell stages is important for the activation of lineage differentiation programs. In contrast to reduction of DP and pro-B cells, Egr-2 enhanced the maturation of DP cells into single positive (SP) T and NKT cells in thymus, and immature B cells into mature B cells in bone marrow. CONCLUSIONS: Our results demonstrate that Egr-2 expressed in restricted stages of lymphocyte development plays a dynamic, but similar role for the development of T, NKT and B cells.This article is provided by the Brunel Open Access publishing fund

Observation of contemporaneous optical radiation from a gamma-ray burst

The origin of gamma-ray bursts (GRBs) has been enigmatic since their discovery. The situation improved dramatically in 1997, when the rapid availability of precise coordinates for the bursts allowed the detection of faint optical and radio afterglows - optical spectra thus obtained have demonstrated conclusively that the bursts occur at cosmological distances. But, despite efforts by several groups, optical detection has not hitherto been achieved during the brief duration of a burst. Here we report the detection of bright optical emission from GRB990123 while the burst was still in progress. Our observations begin 22 seconds after the onset of the burst and show an increase in brightness by a factor of 14 during the first 25 seconds; the brightness then declines by a factor of 100, at which point (700 seconds after the burst onset) it falls below our detection threshold. The redshift of this burst, approximately 1.6, implies a peak optical luminosity of 5 times 10^{49} erg per second. Optical emission from gamma-ray bursts has been generally thought to take place at the shock fronts generated by interaction of the primary energy source with the surrounding medium, where the gamma-rays might also be produced. The lack of a significant change in the gamma-ray light curve when the optical emission develops suggests that the gamma-rays are not produced at the shock front, but closer to the site of the original explosion.Comment: 10 pages, 2 figures. Accepted for publication in Nature. For additional information see http://www.umich.edu/~rotse

Stability Analysis of Frame Slotted Aloha Protocol

Frame Slotted Aloha (FSA) protocol has been widely applied in Radio Frequency Identification (RFID) systems as the de facto standard in tag identification. However, very limited work has been done on the stability of FSA despite its fundamental importance both on the theoretical characterisation of FSA performance and its effective operation in practical systems. In order to bridge this gap, we devote this paper to investigating the stability properties of FSA by focusing on two physical layer models of practical importance, the models with single packet reception and multipacket reception capabilities. Technically, we model the FSA system backlog as a Markov chain with its states being backlog size at the beginning of each frame. The objective is to analyze the ergodicity of the Markov chain and demonstrate its properties in different regions, particularly the instability region. By employing drift analysis, we obtain the closed-form conditions for the stability of FSA and show that the stability region is maximised when the frame length equals the backlog size in the single packet reception model and when the ratio of the backlog size to frame length equals in order of magnitude the maximum multipacket reception capacity in the multipacket reception model. Furthermore, to characterise system behavior in the instability region, we mathematically demonstrate the existence of transience of the backlog Markov chain.Comment: 14 pages, submitted to IEEE Transaction on Information Theor

Effects of local hypothermia-rewarming on physiology, metabolism and inflammation of acutely injured human spinal cord.

In five patients with acute, severe thoracic traumatic spinal cord injuries (TSCIs), American spinal injuries association Impairment Scale (AIS) grades A-C, we induced cord hypothermia (33 °C) then rewarming (37 °C). A pressure probe and a microdialysis catheter were placed intradurally at the injury site to monitor intraspinal pressure (ISP), spinal cord perfusion pressure (SCPP), tissue metabolism and inflammation. Cord hypothermia-rewarming, applied to awake patients, did not cause discomfort or neurological deterioration. Cooling did not affect cord physiology (ISP, SCPP), but markedly altered cord metabolism (increased glucose, lactate, lactate/pyruvate ratio (LPR), glutamate; decreased glycerol) and markedly reduced cord inflammation (reduced IL1β, IL8, MCP, MIP1α, MIP1β). Compared with pre-cooling baseline, rewarming was associated with significantly worse cord physiology (increased ICP, decreased SCPP), cord metabolism (increased lactate, LPR; decreased glucose, glycerol) and cord inflammation (increased IL1β, IL8, IL4, IL10, MCP, MIP1α). The study was terminated because three patients developed delayed wound infections. At 18-months, two patients improved and three stayed the same. We conclude that, after TSCI, hypothermia is potentially beneficial by reducing cord inflammation, though after rewarming these benefits are lost due to increases in cord swelling, ischemia and inflammation. We thus urge caution when using hypothermia-rewarming therapeutically in TSCI

Comparison of Sentiment Analysis and User Ratings in Venue Recommendation

Venue recommendation aims to provide users with venues to visit, taking into account historical visits to venues. Many venue recommendation approaches make use of the provided users’ ratings to elicit the users’ preferences on the venues when making recommendations. In fact, many also consider the users’ ratings as the ground truth for assessing their recommendation performance. However, users are often reported to exhibit inconsistent rating behaviour, leading to less accurate preferences information being collected for the recommendation task. To alleviate this problem, we consider instead the use of the sentiment information collected from comments posted by the users on the venues as a surrogate to the users’ ratings. We experiment with various sentiment analysis classifiers, including the recent neural networks-based sentiment analysers, to examine the effectiveness of replacing users’ ratings with sentiment information. We integrate the sentiment information into the widely used matrix factorization and GeoSoCa multi feature-based venue recommendation models, thereby replacing the users’ ratings with the obtained sentiment scores. Our results, using three Yelp Challenge-based datasets, show that it is indeed possible to effectively replace users’ ratings with sentiment scores when state-of-the-art sentiment classifiers are used. Our findings show that the sentiment scores can provide accurate user preferences information, thereby increasing the prediction accuracy. In addition, our results suggest that a simple binary rating with ‘like’ and ‘dislike’ is a sufficient substitute of the current used multi-rating scales for venue recommendation in location-based social networks

Strained graphene structures: from valleytronics to pressure sensing

Due to its strong bonds graphene can stretch up to 25% of its original size without breaking. Furthermore, mechanical deformations lead to the generation of pseudo-magnetic fields (PMF) that can exceed 300 T. The generated PMF has opposite direction for electrons originating from different valleys. We show that valley-polarized currents can be generated by local straining of multi-terminal graphene devices. The pseudo-magnetic field created by a Gaussian-like deformation allows electrons from only one valley to transmit and a current of electrons from a single valley is generated at the opposite side of the locally strained region. Furthermore, applying a pressure difference between the two sides of a graphene membrane causes it to bend/bulge resulting in a resistance change. We find that the resistance changes linearly with pressure for bubbles of small radius while the response becomes non-linear for bubbles that stretch almost to the edges of the sample. This is explained as due to the strong interference of propagating electronic modes inside the bubble. Our calculations show that high gauge factors can be obtained in this way which makes graphene a good candidate for pressure sensing.Comment: to appear in proceedings of the NATO Advanced Research Worksho