Miracle-dz/UniFAR-FTUs huggingface dataset:
Genetic control of brain morphogenesis through Otx gene dosage requirement.

Understanding the genetic mechanisms that control patterning of the vertebrate brain represents a major challenge for developmental neurobiology. Previous data suggest that Otx1 and Otx2, two murine homologs of the Drosophila orthodenticle (otd) gene, might both contribute to brain morphogenesis. To gain insight into this possibility, the level of OTX proteins was modified by altering in vivo the Otx gene dosage. Here we report that Otx genes may cooperate in brain morphogenesis and that a minimal level of OTX proteins, corresponding either to one copy each of Otx1 and Otx2, or to only two copies of Otx2, is required for proper regionalization and subsequent patterning of the developing brain. Thus, as revealed by anatomical and molecular analyses, only Otx1-/-; Otx2+/- embryos lacked mesencephalon, pretectal area, dorsal thalamus and showed an heavy reduction of the Ammon's horn, while the metencephalon was dramatically enlarged occupying the mesencencephalic area. In 8.5 days post coitum (d.p.c.) Otx1-/-; Otx2+/- embryos, the expression patterns of mesencephalic-metencephalic (mes-met) markers such as En-1 and Wnt-1 confirmed the early presence of the area fated to give rise to mesencephalon and metencephalon while Fgf-8 transcripts were improperly localized in a broader domain. Thus, in Otx1-/-; Otx2+/- embryos, Fgf-8 misexpression is likely to be the consequence of a reduced level of specification between mes-met primitive neuroepithelia that triggers the following repatterning involving the transformation of mesencephalon into metencephalon, the establishment of an isthmic-like structure in the caudal diencephalon and, by 12.5 d.p.c. , the telencephalic expression of Wnt-1 and En-2. Taken together these findings support the existence of a molecular mechanism depending on a precise threshold of OTX proteins that is required to specify early regional diversity between adjacent mes-met territories and, in turn, to allow the correct positioning of the isthmic organizer.
RETRACTION: Erlotinib Induces Mitochondrial-Mediated Apoptosis in Human H3255 Non-Small-Cell Lung Cancer Cells with Epidermal Growth Factor ReceptorL858R Mutation through Mitochondrial Oxidative Phosphorylation-Dependent Activation of BAX and BAK

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib shows potent antitumor activity in some non-small-cell lung cancer (NSCLC) cell lines and is approved by the Food and Drug Administration as second and third line treatment for NSCLC. However, the molecular mechanisms by which erlotinib induces apoptosis remain to be elucidated. Here, we investigated the effect of erlotinib on apoptotic signal pathways in H3255 cells with the EGFRL858R mutation. Erlotinib induces apoptosis associated with the activation of caspases in a dose- and time-dependent manner. Erlotinib did not alter the expression of apoptotic receptors FAS and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), although it induced caspase-8 activation and BID cleavage. In addition, cell death caused by erlotinib was not prevented by coincubation with FAS and TRAIL antagonists, ZB-4 monoclonal antibody and TRAIL/Fc recombinant, suggesting that erlotinib-induced apoptosis is not associated with receptor-mediated pathways. Erlotinib induces loss of mitochondrial membrane potential and release of cytochrome c and second mitochondria-derived activator of caspases/direct IAP binding protein with low pI from mitochondria. Furthermore, erlotinib causes BAX translocation to mitochondria, BAX and BAK conformational changes, and oligomerization. Erlotinib did not induce reactive oxygen species generation, and cotreatment with antioxidants did not alter erlotinib-induced activation of BAX and BAK and apoptosis. However, cotreatment with inhibitors of mitochondrial oxidative phosphorylation significantly blocked erlotinib-induced activation of BAX and BAK and cell death. Benzyloxycarbiny-VAD-fluoromethyl ketone had no effect on erlotinib-induced BAX and BAK activation but effectively prevented apoptosis. Overexpression of BCL-2 caused a significant attenuation of erlotinib-induced cell death, but no effect on BAX and BAK activation. Down-regulation of BAX and BAK gene expression with small interfering RNA led to an effective reduction of erlotinib-induced apoptosis. Our data indicate that activation of BAX and BAK plays a critical role in the initiation of erlotinib-induced apoptotic cascades.
An Automatic Seeded Region Growing for 2D Biomedical Image Segmentation

In this paper, an automatic seeded region growing algorithm is proposed for cellular image segmentation. First, the regions of interest (ROIs) extracted from the preprocessed image. Second, the initial seeds are automatically selected based on ROIs extracted from the image. Third, the most reprehensive seeds are selected using a machine learning algorithm. Finally, the cellular image is segmented into regions where each region corresponds to a seed. The aim of the proposed is to automatically extract the Region of Interests (ROI) from in the cellular images in terms of overcoming the explosion, under segmentation and over segmentation problems. Experimental results show that the proposed algorithm can improve the segmented image and the segmented results are less noisy as compared to some existing algorithms.
Differential Regulation of AMPA Receptor Trafficking by Neurabin-Targeted Synaptic Protein Phosphatase-1 in Synaptic Transmission and Long-Term Depression in Hippocampus

Filamentous actin binding protein neurabin I (NrbI) targets protein phosphatase-1 (PP1) to specific postsynaptic microdomains, exerting critical control over AMPA receptor (AMPAR)-mediated synaptic transmission. NrbI-targeted synaptic PP1, which promotes synaptic depression upon long-term depression (LTD) stimuli, serves to prevent synaptic depression under basal conditions. The present studies investigate this opposite regulation of AMPAR trafficking during basal synaptic transmission and LTD by expressing NrbI or NrbI mutant, which is defective in PP1 binding, in hippocampal slice or neuron cultures. We find that expression of the NrbI mutant to interfere with PP1 targeting dramatically reduces basal synaptic transmission, which is correlated with the reduction in surface expression of AMPA subtype glutamate receptor (GluR) 1 and GluR2 subunits. Biochemical analysis demonstrates that the NrbI mutant selectively increases the phosphorylation of GluR2 at C-terminal consensus PKC site, serine 880, which is known to favor GluR2 interaction with PDZ (postsynaptic density 95/Discs large/zona occludens 1) protein PICK1 (protein interacting with C kinase-1). Inhibition of PKC activity or GluR2–PICK1 interaction completely reverses the synaptic depression in neurons expressing the NrbI mutant, suggesting that NrbI-targeted synaptic PP1 stabilizes the basal transmission by negatively controlling PKC phosphorylation of GluR2 and the subsequent PICK1-mediated decrease in GluR2-containing AMPAR surface expression. Distinct from basal transmission, blocking GluR2–PICK1 interaction or PKC activity produces minimal effects on LTD in NrbI-expressing neurons. Instead, NrbI-targeted PP1 facilitates LTD by dephosphorylating GluR1 at both serine 845 and serine 831, with GluR2 serine 880 phosphorylation unaltered. Our studies thus elucidate that NrbI-targeted PP1, in response to distinct synaptic activities, regulates the synaptic trafficking of specific AMPAR subunits.
Online Square Detection

The online square detection problem is to detect the first occurrence of a square in a string whose characters are provided as input one at a time. Recall that a square is a string that is a concatenation of two identical strings. In this paper we present an algorithm solving this problem in $O(n\log\sigma)$ time and linear space on ordered alphabet, where $\sigma$ is the number of different letters in the input string. Our solution is relatively simple and does not require much memory unlike the previously known online algorithm with the same working time. Also we present an algorithm working in $O(n\log n)$ time and linear space on unordered alphabet, though this solution does not outperform the previously known result with the same time bound.
[13C]bicarbonate kinetics in humans: intra- vs. interindividual variations.

A comprehensive multicompartmental analysis of HCO-3 kinetics was carried out on five normal, resting, fasted adults on three separate occasions at 1-wk to 1-mo intervals to obtain a set of bicarbonate kinetic parameters and estimates of their inter- and intraindividual variations for use in the design and analysis of future nutrient oxidation studies. Following a rapid bolus of NaH13CO3 (10 mumol . kg-1 iv), the decay of 13C enrichment of breath CO2 could be described by a three-exponential decay process and a linearly time-dependent term that accounted for changes in the 13C enrichment of metabolic fuels. The data were fitted subsequently to a mammillary multicompartmental model that consisted of a central pool and two peripheral pools of 3,310, 3,490, and 8,070 mumol . kg-1 HCO-3-CO2. Labeled CO2 was eliminated from the central pool by respiratory and nonrespiratory routes at rates of 101 and 97 mumol . kg-1 . min-1, respectively. The within-subject and among-subject variances were similar for the amount of freely exchangeable bicarbonate (14,870 mumol . kg-1), CO2 output (101 mumol . kg-1 . min-1), bicarbonate flux (198 mumol . kg-1 . min-1), and the fraction of administered bicarbonate recovered in breath (0.51). Comparison of variances associated with the assignment of a population mean value to a new subject and the variance associated with the use of a value obtained in the same individual on another day indicated that there was no advantage to making a determination on an alternate day over using a population value. Efforts should be made to compile population values for bicarbonate kinetics in different age groups and metabolic, nutritional, and pathological states for use in interpretation of nutrient oxidation data.
IL-7 receptor signaling is necessary for stage transition in adult B cell development through up-regulation of EBF

Cytokine receptor signals have been suggested to stimulate cell differentiation during hemato/lymphopoiesis. Such action, however, has not been clearly demonstrated. Here, we show that adult B cell development in IL-7 −/− and IL-7Rα2/− mice is arrested at the pre–pro-B cell stage due to insufficient expression of the B cell–specific transcription factor EBF and its target genes, which form a transcription factor network in determining B lineage specification. EBF expression is restored in IL-7 −/− pre–pro-B cells upon IL-7 stimulation or in IL-7Rα−/− pre–pro-B cells by activation of STAT5, a major signaling molecule downstream of the IL-7R signaling pathway. Furthermore, enforced EBF expression partially rescues B cell development in IL-7Rα−/− mice. Thus, IL-7 receptor signaling is a participant in the formation of the transcription factor network during B lymphopoiesis by up-regulating EBF, allowing stage transition from the pre–pro-B to further maturational stages.
Not a Humbug: the evolution of patient-centred medical decision-making

This ‘Christmas Issue’-type paper uses the framework of ‘A Christmas Carol’ to tell about the evolution of decision-making in evidence-based medicine (EBM). The Ghost of the Past represents paternalistic medicine, the Ghost of the Present symbolises EBM, while the Ghost of the Future serves as a patient-centred system where research data and tools of decision science are jointly used to make optimal medical decisions for individual patients. We argue that this shift towards a patient-centred approach to EBM and medical care is the next step in the evolution of medical decision-making, which would help to empower patients with the capability to make educated decisions throughout the course of their medical treatment.
The QV family compared to other reinforcement learning algorithms

This paper describes several new online model-free reinforcement learning (RL) algorithms. We designed three new reinforcement algorithms, namely: QV2, QVMAX, and QVMAX2, that are all based on the QV-learning algorithm, but in contrary to QV-learning, QVMAX and QVMAX2 are off-policy RL algorithms and QV2 is a new on-policy RL algorithm. We experimentally compare these algorithms to a large number of different RL algorithms, namely: Q-learning, Sarsa, R-learning, Actor-Critic, QV-learning, and ACLA. We show experiments on five maze problems of varying complexity. Furthermore, we show experimental results on the cart pole balancing problem. The results show that for different problems, there can be large performance differences between the different algorithms, and that there is not a single RL algorithm that always performs best, although on average QV-learning scores highest.
A Style Adaptation Technique for Speech Synthesis Using HSMM and Suprasegmental Features

This paper proposes a technique for synthesizing speech with a desired speaking style and/or emotional expression, based on model adaptation in an HMM-based speech synthesis framework. Speaking styles and emotional expressions are characterized by many segmental and suprasegmental features in both spectral and prosodic features. Therefore, it is essential to take account of these features in the model adaptation. The proposed technique called style adaptation, deals with this issue. Firstly, the maximum likelihood linear regression (MLLR) algorithm, based on a framework of hidden semi-Markov model (HSMM) is presented to provide a mathematically rigorous and robust adaptation of state duration and to adapt both the spectral and prosodic features. Then, a novel tying method for the regression matrices of the MLLR algorithm is also presented to allow the incorporation of both the segmental and suprasegmental speech features into the style adaptation. The proposed tying method uses regression class trees with contextual information. From the results of several subjective tests, we show that these techniques can perform style adaptation while maintaining naturalness of the synthetic speech.
Simultaneous Detection of Mycobacterium leprae and Its Susceptibility to Dapsone Using DNA Heteroduplex Analysis

ABSTRACT Currently recommended control measures for treating leprosy with multidrug therapy should control the spread of drug-resistant strains; however, dapsone (DDS) resistance continues to be reported. Comprehensive estimates of drug-resistant leprosy are difficult to obtain due to the cumbersome nature of the conventional drug susceptibility testing method using mouse footpad inoculation, which requires at least 6 months to obtain results. Recently, it has been determined that DDS-resistant strains contain missense mutations in codon 53 or 55 of the folP1 gene of Mycobacterium leprae, and definitive evidence linking these mutations with DDS resistance in M. leprae has been obtained. Based on these mutations, a heteroduplex DDS M. leprae (HD-DDS-ML) assay was developed for the simultaneous detection of M. lepraeand of its susceptibility to DDS. The assay relies on the PCR amplification of an M. leprae-specific 231-bp fragment offolP1 containing codons 53 and 55. The PCR products are allowed to anneal to a universal heteroduplex generator, and the separation of the resultant DNA duplexes is accomplished by polyacrylamide gel electrophoresis. M. leprae was detected in crude cell lysates of skin biopsy specimen homogenates from eight leprosy patients and from M. leprae-infected mouse or armadillo tissues infected with 14 separate strains using the HD-DDS-ML assay. The assay was specific for M. leprae in a comparison with results obtained from 14 species of mycobacteria other thanM. leprae and four bacterial species known to colonize human skin. The HD-DDS-ML assay detected as few as 100 M. leprae organisms present in homogenates of human skin and demonstrated a 93% correlation with DDS susceptibility as determined by both DNA sequencing of folP1 and mouse footpad susceptibility testing. The HD-DDS-ML assay provides a new tool for the simultaneous detection of M. leprae and of its susceptibility to DDS from a single specimen. The assay should prove useful for drug resistance surveillance in leprosy control programs when combined with similar molecular tests developed for other drug resistance markers.
Gas near active galactic nuclei: A search for the 4.7 µm CO band

In order to constrain the properties of dense and warm gas around active galactic nuclei, we have searched Infrared Space Observatory spectra of local active galactic nuclei (AGN) for the signature of the 4.7 μ m fundamental ro-vibrational band of carbon monoxide. Low resolution spectra of 31 AGN put upper limits on the presence of wide absorption bands corresponding to absorption by large columns of warm and dense gas against the nuclear dust continuum. High resolution ($R\sim2500$) spectra of NGC 1068 detect no significant absorption or emission in individual lines, to a 3 σ limit of 7% of the continuum. The limits set on CO absorption in local AGN are much lower than the recent Spitzer Space Telescope detection of strong CO absorption by dense and warm gas in the obscured ultraluminous infrared galaxy IRAS F00183-7111, despite evidence for dense material on parsec scales near an AGN in both types of objects. This suggests that such deep absorptions are not intimately related to the obscuring “torus” material invoked in local AGN, but rather are a signature of the peculiar conditions in the circumnuclear region of highly obscured infrared galaxies like IRAS F00183-7111. They may reflect fully covered rather than torus geometries.
Teaching against the grain: multi‐disciplinary teamwork effectively delivers a successful undergraduate unit in sustainable development

A team‐taught interdisciplinary undergraduate unit in Sustainable Development has been developed and run over the past two years at the University of Bristol. This has been a unique initiative for this university to take. As in most other research‐intensive higher education institutions, teaching generally follows rather traditional disciplinary conventions, operating within departmental bounds. The initiative was unusual – and indeed ambitious – enough to gain the Higher Education Environmental Performance Improvement (HEEPI) Green Gown Award in teaching for 2007 (HEEPI is a project supported by the Higher Education Founding Council for England; http://www.heepi.org.uk/green_gown_awards.htm). There are both challenges and pleasures in designing and delivering a team‐taught unit in a traditional university setting. This experience is outlined and evaluated here, giving consideration to both the practical and the more fundamentally philosophical issues encountered in the process.
SDF: A Sign Description Framework for Cross-Context Information Resource Representation and Interchange

While Internet is experiencing a drastic change, semantic representation study becomes more and more important in electronic business and enterprise systems. To semantically represent information resources, this paper proposes a novel Sign Description Framework, which is an abstract specification that represents any object in reality as signs. Based on a quaternary model of sign in semiotics, the proposed framework has several advantages such as non-ambiguity of resource representation in meaning, easy resource modeling, and easy cross-context heterogeneous resource mapping.
Agreement between Theory and Measurement in Quantification of Ammonia-Oxidizing Bacteria

ABSTRACT Autotrophic ammonia-oxidizing bacteria (AOB) are of vital importance to wastewater treatment plants (WWTP), as well as being an intriguing group of microorganisms in their own right. To date, corroboration of quantitative measurements of AOB by fluorescence in situ hybridization (FISH) has relied on assessment of the ammonia oxidation rate per cell, relative to published values for cultured AOB. Validation of cell counts on the basis of substrate transformation rates is problematic, however, because published cell-specific ammonia oxidation rates vary by over two orders of magnitude. We present a method that uses FISH in conjunction with confocal scanning laser microscopy to quantify AOB in WWTP, where AOB are typically observed as microcolonies. The method is comparatively simple, requiring neither detailed cell counts or image analysis, and yet it can give estimates of either cell numbers or biomass. Microcolony volume and diameter were found to have a log-normal distribution. We were able to show that virtually all (>96%) of the AOB biomass occurred as microcolonies. Counts of microcolony abundance and measurement of their diameter coupled with a calibration of microcolony dimensions against cell numbers or AOB biomass were used to determine AOB cell numbers and biomass in WWTP. Cell-specific ammonia oxidation rates varied between plants by over three orders of magnitude, suggesting that cell-specific ammonia oxidation is an important process variable. Moreover, when measured AOB biomass was compared with process-based estimates of AOB biomass, the two values were in agreement.
Exchangeable, Gibbs and equilibrium measures for Markov subshifts

We study a class of strongly irreducible, multidimensional, topological Markov shifts, comparing two notions of ‘symmetric measure’: exchangeability and the Gibbs (or conformal) property. We show that equilibrium measures for such shifts (unique and weak Bernoulli in the one-dimensional case) exhibit a variety of spectral properties.
Botanical and Phytochemical Therapy of Acne: A Systematic Review

Acne is prevalent among adolescents and adults with significant psychological effects. Standard oral and topical therapies can have significant side effects including skin irritation, gastrointestinal upset, and the development of drug‐resistant bacteria. The use of botanicals and phytochemicals in dermatological products is increasingly popular, and many patients are turning to these alternative therapies for treatment of acne. This study aimed to systematically review clinical studies that have investigated the use of botanical agents in the treatment of acne. PubMed and Embase databases were searched in March 2013 for trials assessing botanical therapies in the treatment of acne vulgaris. Data from these trials are presented, and methodology of each study is assessed. Twenty‐three trials met inclusion criteria. Interventions included plant extracts, herbal formulations, and phytochemicals. All studies reported favorable results, and several showed equal or superior treatment to standard therapies. No serious adverse events were reported. Few studies were methodologically rigorous. Each botanical was studied in only one or two trials. Botanicals are promising therapies for acne vulgaris although further research is warranted, especially with regard to severe acne and acne resistant to conventional therapy. There is a need for standardized methods for grading acne and assessing therapeutic effects. Copyright © 2014 John Wiley & Sons, Ltd.
The 2-codeword screening test for lasso problems

Solving a lasso problem is a practical approach for acquiring a sparse representation of a signal with respect to a given dictionary. Driven by the demand for sparse representations over large-scale data in machine learning and statistics, we explore lasso screening tests. These enhance solution efficiency via the elimination of codewords absent in the optimal solution prior to detailed computation. On basis of the concept of a region test and the recently introduced dome test, we propose the 2-codeword test, which uses two codewords together in a correlation screening test. In addition to the rejection rate as the performance measure, we introduce an innovative way to access the performance of a screening test, called the uncertainty measure, via a comparison with the optimal test.