Impact of contact overlap on transconductance and noise in organic electrochemical transistors

Abstract Organic electrochemical transistors (OECTs) from poly(3,4-ethylenedioxythiophene) doped with polystyrene sulfonate (PEDOT:PSS) are used as amplifying transducers for bioelectronics. Although the impact on performance of device geometry parameters such as channel area and thickness has been widely explored, the overlap between the semiconductor film and the source and drain contacts has not been considered. Here we vary this overlap and explore its impact on transconductance and noise. We show that increasing contact overlap does not alter the magnitude of the steady-state transconductance but it does decreases the cut-off frequency. Noise was found to be independent of contact overlap and to vary according to the charge noise model. The results show that high-quality contacts can be established in PEDOT:PSS OECTs with minimal overlap.</jats:p

Effect of channel thickness on noise in organic electrochemical transistors

Organic electrochemical transistors (OECTs) have been widely used as transducers in electrophysiology and other biosensing applications. Their identifying characteristic is a transconductance that increases with channel thickness, and this provides a facile mechanism to achieve high signal amplification. However, little is known about their noise behavior. Here, we investigate noise and extract metrics for the signal-to-noise ratio and limit of detection in OECTs with different channel thicknesses. These metrics are shown to improve as the channel thickness increases, demonstrating that OECTs can be easily optimized to show not only high amplification, but also low noise.</jats:p

Categorical Dimensions of Human Odor Descriptor Space Revealed by Non-Negative Matrix Factorization

In contrast to most other sensory modalities, the basic perceptual dimensions of olfaction remain unclear. Here, we use non-negative matrix factorization (NMF) – a dimensionality reduction technique – to uncover structure in a panel of odor profiles, with each odor defined as a point in multi-dimensional descriptor space. The properties of NMF are favorable for the analysis of such lexical and perceptual data, and lead to a high-dimensional account of odor space. We further provide evidence that odor dimensions apply categorically. That is, odor space is not occupied homogenously, but rather in a discrete and intrinsically clustered manner. We discuss the potential implications of these results for the neural coding of odors, as well as for developing classifiers on larger datasets that may be useful for predicting perceptual qualities from chemical structures

Nucleotide Polymorphisms in the Canine Noggin Gene and Their Distribution Among Dog (Canis lupus familiaris) Breeds

Noggin (NOG) is an important regulator for the signaling of bone morphogenetic proteins. In this study, we sequenced the complete coding sequence of the canine NOG gene and characterized the nucleotide polymorphisms. The sequence length varied from 717 to 729 bp, depending on the number of a 6-bp tandem repeat unit (GGCGCG), an insertion that has not been observed in other mammalian NOG genes investigated to date. It results in extensions of (Gly–Ala)3–5 in the putative NOG protein. To survey the distribution of these tandem repeat polymorphisms, we analyzed 126 individuals in seven dog breeds. We identified only three alleles: (GGCGCG)3, (GGCGCG)4, and (GGCGCG)5. Although the allele frequencies were remarkably different among the breeds, the three alleles were present in all seven of the breeds and did not show any deviation from Hardy–Weinberg equilibrium

TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT.

Intrinsic and acquired resistance to chemotherapy is the fundamental reason for treatment failure for many cancer patients. The identification of molecular mechanisms involved in drug resistance or sensitization is imperative. Here we report that tribbles homologue 2 (TRIB2) ablates forkhead box O activation and disrupts the p53/MDM2 regulatory axis, conferring resistance to various chemotherapeutics. TRIB2 suppression is exerted via direct interaction with AKT a key signalling protein in cell proliferation, survival and metabolism pathways. Ectopic or intrinsic high expression of TRIB2 induces drug resistance by promoting phospho-AKT (at Ser473) via its COP1 domain. TRIB2 expression is significantly increased in tumour tissues from patients correlating with an increased phosphorylation of AKT, FOXO3a, MDM2 and an impaired therapeutic response. This culminates in an extremely poor clinical outcome. Our study reveals a novel regulatory mechanism underlying drug resistance and suggests that TRIB2 functions as a regulatory component of the PI3K network, activating AKT in cancer cells

Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

Speeding up the Consensus Clustering methodology for microarray data analysis

<p>Abstract</p> <p>Background</p> <p>The inference of the number of clusters in a dataset, a fundamental problem in Statistics, Data Analysis and Classification, is usually addressed via internal validation measures. The stated problem is quite difficult, in particular for microarrays, since the inferred prediction must be sensible enough to capture the inherent biological structure in a dataset, e.g., functionally related genes. Despite the rich literature present in that area, the identification of an internal validation measure that is both fast and precise has proved to be elusive. In order to partially fill this gap, we propose a speed-up of <monospace>Consensus</monospace> (Consensus Clustering), a methodology whose purpose is the provision of a prediction of the number of clusters in a dataset, together with a dissimilarity matrix (the consensus matrix) that can be used by clustering algorithms. As detailed in the remainder of the paper, <monospace>Consensus</monospace> is a natural candidate for a speed-up.</p> <p>Results</p> <p>Since the time-precision performance of <monospace>Consensus</monospace> depends on two parameters, our first task is to show that a simple adjustment of the parameters is not enough to obtain a good precision-time trade-off. Our second task is to provide a fast approximation algorithm for <monospace>Consensus</monospace>. That is, the closely related algorithm <monospace>FC</monospace> (Fast Consensus) that would have the same precision as <monospace>Consensus</monospace> with a substantially better time performance. The performance of <monospace>FC</monospace> has been assessed via extensive experiments on twelve benchmark datasets that summarize key features of microarray applications, such as cancer studies, gene expression with up and down patterns, and a full spectrum of dimensionality up to over a thousand. Based on their outcome, compared with previous benchmarking results available in the literature, <monospace>FC</monospace> turns out to be among the fastest internal validation methods, while retaining the same outstanding precision of <monospace>Consensus</monospace>. Moreover, it also provides a consensus matrix that can be used as a dissimilarity matrix, guaranteeing the same performance as the corresponding matrix produced by <monospace>Consensus</monospace>. We have also experimented with the use of <monospace>Consensus</monospace> and <monospace>FC</monospace> in conjunction with <monospace>NMF</monospace> (Nonnegative Matrix Factorization), in order to identify the correct number of clusters in a dataset. Although <monospace>NMF</monospace> is an increasingly popular technique for biological data mining, our results are somewhat disappointing and complement quite well the state of the art about <monospace>NMF</monospace>, shedding further light on its merits and limitations.</p> <p>Conclusions</p> <p>In summary, <monospace>FC</monospace> with a parameter setting that makes it robust with respect to small and medium-sized datasets, i.e, number of items to cluster in the hundreds and number of conditions up to a thousand, seems to be the internal validation measure of choice. Moreover, the technique we have developed here can be used in other contexts, in particular for the speed-up of stability-based validation measures.</p

Early transcriptional response in the jejunum of germ-free piglets after oral infection with virulent rotavirus

Germ-free piglets were orally infected with virulent rotavirus to collect jejunal mucosal scrapings at 12 and 18 hours post infection (two piglets per time point). IFN-gamma mRNA expression was stimulated in the mucosa of all four infected piglets, indicating that they all responded to the rotavirus infection. RNA pools prepared from two infected piglets were used to compare whole mucosal gene expression at 12 and 18 hpi to expression in uninfected germ-free piglets (n = 3) using a porcine intestinal cDNA microarray. Microarray analysis identified 13 down-regulated and 17 up-regulated genes. Northern blot analysis of a selected group of genes confirmed the data of the microarray. Genes were functionally clustered in interferon-regulated genes, proliferation/differentiation genes, apoptosis genes, cytoskeleton genes, signal transduction genes, and enterocyte digestive, absorptive, and transport genes. Down-regulation of the transport gene cluster reflected in part the loss of rotavirus-infected enterocytes from the villous tips. Data mining suggested that several genes were regulated in lower- or mid-villus immature enterocytes and goblet cells, probably to support repair of the damaged epithelial cell layer at the villous tips. Furthermore, up-regulation was observed for IFN-γ induced guanylate binding protein 2, a protein that effectively inhibited VSV and EMCV replication in vitro (Arch Virol 150:1213–1220, 2005). This protein may play a role in the small intestine’s innate defense against enteric viruses like rotavirus

New Insights into the Genetic Regulation of Homologue Disjunction in Mammalian Oocytes

Mammalian oocytes execute a unique meiotic programme involving 2 arrest stages and an unusually protracted preamble to chromosome segregation during the first meiotic division (meiosis I). How mammalian oocytes successfully navigate their exceptional meiotic journey has long been a question of immense interest. Understanding the minutiae of female mammalian meiosis I is not merely of academic interest as 80–90% of human aneuploidy is the consequence of errors arising at this particular stage of oocyte maturation, a stage with a peculiar vulnerability to aging. Recent evidence indicates that oocytes employ many of the same cast of proteins during meiosis I as somatic cells do during mitosis, often to execute similar tasks, but intriguingly, occasionally delegate them to unexpected and unprecedented roles. This is epitomised by the master cell-cycle regulon, the anaphase-promoting complex or cyclosome (APC/C), acting in concert with a critical APC/C-targeted surveillance mechanism, the spindle assembly checkpoint (SAC). Together, the APC/C and the SAC are among the most influential entities overseeing the fidelity of cell-cycle progression and the precision of chromosome segregation. Here I review the current status of pivotal elements underpinning homologue disjunction in mammalian oocytes including spindle assembly, critical biochemical anaphase-initiating events, APC/C activity and SAC signalling along with contemporary findings relevant to progressive oocyte SAC dysfunction as a model for age-related human aneuploidy

A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features.

Childhood onset clinical syndromes involving intellectual disability and dysmorphic features, such as polydactyly, suggest common developmental pathways link seemingly unrelated phenotypes. We identified a consanguineous family of Saudi origin with varying complex features including intellectual disability, speech delay, facial dysmorphism and polydactyly. Combining, microarray based comparative genomic hybridisation (CGH) to identify regions of homozygosity, with exome sequencing, led to the identification of homozygous mutations in five candidate genes (RSPH6A, ANKK1, AMOTL1, ALKBH8, TRAPPC6A), all of which appear to be pathogenic as predicted by Proven, SIFT and PolyPhen2 and segregate perfectly with the disease phenotype. We therefore looked for differences in expression levels of each protein in HEK293 cells, expressing either the wild-type or mutant full-length cDNA construct. Unexpectedly, wild-type TRAPPC6A appeared to be unstable, but addition of the proteasome inhibitor MG132 stabilised its expression. Mutations have previously been reported in several members of the TRAPP complex of proteins, including TRAPPC2, TRAPPC9 and TRAPPC11, resulting in disorders involving skeletal abnormalities, intellectual disability, speech impairment and developmental delay. TRAPPC6A joins a growing list of proteins belonging to the TRAPP complex, implicated in clinical syndromes with neurodevelopmental abnormalities