Miracle-dz/UniFAR-FTUs huggingface dataset:
Conditional Forebrain Inactivation of Nicastrin Causes Progressive Memory Impairment and Age-Related Neurodegeneration

Loss of presenilin function in adult mouse brains causes memory loss and age-related neurodegeneration. Since presenilin possesses γ-secretase-dependent and -independent activities, it remains unknown which activity is required for presenilin-dependent memory formation and neuronal survival. To address this question, we generated postnatal forebrain-specific nicastrin conditional knock-out (cKO) mice, in which nicastrin, a subunit of γ-secretase, is inactivated selectively in mature excitatory neurons of the cerebral cortex. nicastrin cKO mice display progressive impairment in learning and memory and exhibit age-dependent cortical neuronal loss, accompanied by astrocytosis, microgliosis, and hyperphosphorylation of the microtubule-associated protein Tau. The neurodegeneration observed in nicastrin cKO mice likely occurs via apoptosis, as evidenced by increased numbers of apoptotic neurons. These findings demonstrate an essential role of nicastrin in the execution of learning and memory and the maintenance of neuronal survival in the brain and suggest that presenilin functions in memory and neuronal survival via its role as a γ-secretase subunit.
Hematopoietic growth factor expression and ATRA sensitivity in acute promyelocytic blast cells.

Acute promyelocytic leukemia (APL) is a homogeneous subgroup of acute myeloid leukemias (AMLs) characterized by the presence of the t(15,17) translocation and the resulting promyelocytic myeloid leukemia/retinoic acid receptor alpha (PML/RAR alpha) fusion proteins. To date APL is the only AML that is sufficiently sensitive to all-trans retinoic acid's (ATRA) differentiating effect. In vivo ATRA alone achieves complete remission in most APL patients. However, failure or partial responses are observed and the molecular basis of the absence of ATRA response in these patients has not been determined. To gain insights in the cell growth and differentiation of APL cells, expression of hematopoietic growth factors (HGF) shown to be produced by leukemic cells (interleukin-1 beta [IL-1 beta], IL-6, tumor necrosis factor alpha (TNF alpha), granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], and IL-3) was studied in 16 APL samples. Twelve APL cases expressed IL-1 beta, IL-6, and TNF alpha, but not G-CSF, GM-CSF, and IL-3. These cases achieved complete remission with ATRA therapy. The four remaining patients (either TNF alpha negative or G-CSF, GM-CSF or IL-3 positive) did not achieve complete remission with ATRA. In all cases, in vivo response to ATRA therapy was correlated to the in vitro differentiation effect of all-trans retinoic acid 10(-6) mol/L. Thus, ATRA differentiation induction was strongly correlated to the HGF expression (P < .0001). These results suggest that the presence or absence of HGF's expression by APL cells may contribute to the therapeutic effect of ATRA in this disease.
Annotating Events in an Emotion Corpus

This paper presents the development of a Chinese event-based emotion corpus. It specifically describes the corpus design, collection and annotation. The proposed annotation scheme provides a consistent way of identifying some emotion-associated events (namely pre-events and post-events). Corpus data show that there are significant interactions between emotions and pre-events as well as that of between emotion and post-events. We believe that emotion as a pivot event underlies an innovative approach towards a linguistic model of emotion as well as automatic emotion detection and classification.
Genetic Background Effects on Disease Onset and Lifespan of the Mutant Dynactin p150Glued Mouse Model of Motor Neuron Disease

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily affecting motor neurons in the central nervous system. Although most cases of ALS are sporadic, about 5–10% of cases are familial (FALS) with approximately 20% of FALS caused by mutations in the Cu/Zn superoxide dismutase (SOD1) gene. We have reported that hSOD1-G93A transgenic mice modeling this disease show a more severe phenotype when the transgene is bred on a pure SJL background and a milder phenotype when bred on a pure B6 background and that these phenotype differences link to a region on mouse Chromosome 17.To examine whether other models of motor neuron degeneration are affected by genetic background, we bred the mutant human dynactin p150Glued (G59S-hDCTN1) transgene onto inbred SJL and B6 congenic lines. This model is based on an autosomal dominant lower motor neuron disease in humans linked to a mutation in the p150Glued subunit of the dynactin complex. As seen in hSOD1-G93A mice, we observed a more severe phenotype with earlier disease onset (p<0.001) and decreased survival (p<0.00001) when the G59S-hDCTN1 transgene was bred onto the SJL background and delayed onset (p<0.0001) with increased survival (p<0.00001) when bred onto the B6 background. Furthermore, B6 mice with an SJL derived chromosome 17 interval previously shown to delay disease onset in hSOD1-G93A mice also showed delays onset in G59S-hDCTN1 mice suggesting that at least some genetic modifiers are shared. We have shown that genetic background influences phenotype in G59S-hDCTN1 mice, in part through a region of chromosome 17 similar to the G93-hSOD1 ALS mouse model. These results support the presence of genetic modifiers in both these models some of which may be shared. Identification of these modifiers will highlight intracellular pathways involved in motor neuron disease and provide new therapeutic targets that may be applicable to motor neuron degeneration.
Different Patterns of Cortical Inputs to Subregions of the Primary Motor Cortex Hand Representation in Cebus apella

The primary motor cortex (M1) plays an essential role in the control of hand movements in primates and is part of a complex cortical sensorimotor network involving multiple premotor and parietal areas. In a previous study in squirrel monkeys, we found that the ventral premotor cortex (PMv) projected mainly to 3 regions within the M1 forearm representation [rostro-medial (RM), rostro-lateral (RL), and caudo-lateral (CL)] with very few caudo-medial (CM) projections. These results suggest that projections from premotor areas to M1 are not uniform, but rather segregated into subregions. The goal of the present work was to study how inputs from diverse areas of the ipsilateral cortical network are organized within the M1 hand representation. In Cebus apella, different retrograde neuroanatomical tracers were injected in 4 subregions of the hand area of M1 (RM, RL, CM, and CL). We found a different pattern of input to each subregion of M1. RM receives inputs predominantly from dorsal premotor cortex, RL from PMv, CM from area 5, and CL from area 2. These results support that the M1 hand representation is composed of several subregions, each part of a unique cortical network.
Effect of subinhibitory concentrations of ciprofloxacin on Mycobacterium fortuitum mutation rates.

OBJECTIVES Fluoroquinolones have found a place in the management of mycobacterial diseases including tuberculosis. It has been previously shown that subinhibitory concentrations of quinolones increase the mutation rate in Escherichia coli and staphylococci. The purpose of this study is to extend this observation to mycobacteria and to quantify mutation rates. METHODS The mutation rate in Mycobacterium fortuitum to ciprofloxacin, levofloxacin, moxifloxacin, rifampicin, erythromycin and gentamicin resistance was determined when grown with and without various sub-MIC concentrations of ciprofloxacin. RESULTS M. fortuitum exposed to 1/2 MIC ciprofloxacin had an increase in the mutation rate of between 72- and 120-fold when selected on quinolones or other antimycobacterial antibiotics. Smaller, but significant increases in mutation rate were seen when the organism was exposed to lower concentrations (1/4 MIC and 1/8 MIC). CONCLUSIONS These data show that sub-MIC concentrations of fluoroquinolone significantly increase mutation rates and these data suggest that care must be taken to ensure that bacteria are not exposed to subinhibitory concentrations when adding quinolones to a regimen used to treat mycobacterial infection.
A Novel Variable-order Markov Model for Clustering Categorical Sequences

Clustering categorical sequences is an important and difficult data mining task. Despite recent efforts, the challenge remains, due to the lack of an inherently meaningful measure of pairwise similarity. In this paper, we propose a novel variable-order Markov framework, named weighted conditional probability distribution (WCPD), to model clusters of categorical sequences. We propose an efficient and effective approach to solve the challenging problem of model initialization. To initialize the WCPD model, we propose to use a first-order Markov model built on a weighted fuzzy indicator vector representation of categorical sequences, which we call the WFI Markov model. Based on a cascade optimization framework that combines the WCPD and WFI models, we design a new divisive hierarchical clustering algorithm for clustering categorical sequences. Experimental results on data sets from three different domains demonstrate the promising performance of our models and clustering algorithm.
Environmental and developmental controls on specific leaf area are little modified by leaf allometry

Summary 1. Recent work shows that large leaves tend to require higher biomass investments per unit leaf area than small leaves. As a consequence, specific leaf area (SLA), which is a focus trait for a bulk of physiological and ecological research programs, is dependent on leaf size variation. Here, we address whether size dependency alters the outcome of research dealing with SLA responses to environmental or developmental change. 2. We compiled lamina mass ( M ) and surface area ( A ) data for 2158 leaves of 26 species, coming from studies investigating the reaction of SLA to variation in rainfall, growth‐season length, light intensity, atmospheric CO 2 , fire frequency, type of branch and leaf and plant age. We fitted the function M = α A β to the data of each experimental situation separately, and implemented a method to split SLA response as measured in the original study (SLA ∆ m ) into response due to leaf size dependency (SLA ∆ a ), and response due to treatment effects, after controlling for leaf size dependency (SLA ∆ t ). 3. The sign of the reaction did not differ between SLA ∆ m and SLA ∆ t . However, the magnitude of that response changed for most contrasts, though in variable ways. 4. Conclusions of past experiments hold, for the most part, after re-analysis including size dependency. However, given the large heterogeneity found here, we advise that future work investigating SLA be prepared to account for leaf size dependency when the factors under focus are suspected to alter leaf size.
The CHEK2*1100delC Allelic Variant and Risk of Breast Cancer: Screening Results from the Breast Cancer Family Registry

CHEK2, a serine-threonine kinase, is activated in response to agents, such as ionizing radiation, which induce DNA double-strand breaks. Activation of CHEK2 can result in cell cycle checkpoint arrest or apoptosis. One specific variant, CHEK2*1100delC, has been associated with an increased risk of breast cancer. In this population-based study, we screened 2,311 female breast cancer cases and 496 general population controls enrolled in the Ontario and Northern California Breast Cancer Family Registries for this variant (all controls were Canadian). Overall, 30 cases and one control carried the 1100delC allele. In Ontario, the weighted mutation carrier frequency among cases and controls was 1.34% and 0.20%, respectively [odds ratio (OR), 6.65; 95% confidence interval (95% CI), 2.37-18.68]. In California, the weighted population mutation carrier frequency in cases was 0.40%. Across all cases, 1 of 524 non-Caucasians (0.19%) and 29 of 1,775 Caucasians (1.63%) were mutation carriers (OR, 0.12; 95% CI, 0.02-0.89). Among Caucasian cases >45 years age at diagnosis, carrier status was associated with history of benign breast disease (OR, 3.18; 95% CI, 1.30-7.80) and exposure to diagnostic ionizing radiation (excluding mammography; OR, 3.21; 95% CI, 1.13-9.14); compared with women without exposure to ionizing radiation, the association was strongest among women exposed >15 years before diagnosis (OR, 4.28; 95% CI, 1.50-12.20) and among those who received two or more chest X-rays (OR, 3.63; 95% CI, 1.25-10.52). These data supporting the biological relevance of CHEK2 in breast carcinogenesis suggest that further studies examining the joint roles of CHEK2*1100delC carrier status and radiation exposure may be warranted. (Cancer Epidemiol Biomarkers Prev 2006;15(2):348–52)
Whole-Genome Analysis of Transporters in the Plant Pathogen Xylella fastidiosa

SUMMARY The transport systems of the first completely sequenced genome of a plant parasite, Xylella fastidiosa, were analyzed. In all, 209 proteins were classified here as constitutive members of transport families; thus, we have identified 69 new transporters in addition to the 140 previously annotated. The analysis lead to several hints on potential ways of controlling the disease it causes on citrus trees. An ADP:ATP translocator, previously found in intracellular parasites only, was found in X. fastidiosa. A P-type ATPase is missing—among the 24 completely sequenced eubacteria to date, only three (including X. fastidiosa) do not have a P-type ATPase, and they are all parasites transmitted by insect vectors. An incomplete phosphotransferase system (PTS) was found, without the permease subunits—we conjecture either that they are among the hypothetical proteins or that the PTS plays a solely metabolic regulatory role. We propose that the Ttg2 ABC system might be an import system eventually involved in glutamate import rather than a toluene exporter, as previously annotated. X. fastidiosa exhibits fewer proteins with ≥4 α-helical transmembrane spanners than any other completely sequenced prokaryote to date. X. fastidiosa has only 2.7% of all open reading frames identifiable as major transporters, which puts it as the eubacterium having the lowest percentage of open reading frames involved in transport, closer to two archaea, Methanococcus jannaschii (2.4%) and Methanobacterium thermoautotrophicum (2.4%).
Acoustic and syntactical modeling in the ATROS system

Current speech technology allows us to build efficient speech recognition systems. However, model learning of knowledge sources in a speech recognition system is not a closed problem. In addition, lower demand of computational requirements are crucial to building real-time systems. ATROS is an automatic speech recognition system whose acoustic, lexical, and syntactical models can be learnt automatically from training data by using similar techniques. In this paper, an improved version of ATROS which can deal with large smoothed language models and with large vocabularies is presented. This version supports acoustic and syntactical models trained with advanced grammatical inference techniques. It also incorporates new data structures and improved search algorithms to reduce the computational requirements for decoding. The system has been tested on a Spanish task of queries to a geographical database (with a vocabulary of 1,208 words).
The unitary hypothesis: A common neural circuitry for novel manipulations, language, plan-ahead, and throwing?

Plan-ahead becomes necessary for those movements which are over-and-done in less time than it takes for the feedback loop to operate. Natural selection for one of the ballistic movements (hammering, clubbing, and throwing) could evolve a plan-ahead serial buffer for hand-arm commands that would benefit the other ballistic movements as well. This same circuitry may also sequence other muscles (children learning handwriting often screw up their faces and tongues) and so novel oral-facial sequences may also benefit (as might kicking and dancing). An elaborated version of the sequencer may constitute a Darwin Machine that spins scenarios, evolves sentences, and facilitates insight by offline simulation. An example is given of an evolutionary scenario from an apelike ancestor, demonstrating the transition behaviors and growth curve considerations that any such theory needs to have; this particular scenario (involving throwing improvements) also suggests an explanation for the puzzling design of the Acheulean "handaxe. "
Nonequilibrium dynamical transition in the asymmetric exclusion process

Over the last few decades the interests of statistical physicists have broadened to include the detailed quantitative study of many systems – chemical, biological and even social – that were not traditionally part of the discipline. These systems can feature rich and complex spatiotemporal behaviour, often due to continued interaction with the environment and characterised by the dissipation of flows of energy and/or mass. This has led to vigorous research aimed at extending the established theoretical framework and adapting analytical methods that originate in the study of systems at thermodynamic equilibrium to deal with out-of-equilibrium situations, which are much more prevalent in nature. This thesis focuses on a microscopic model known as the asymmetric exclusion process, or ASEP, which describes the stochastic motion of particles on a one-dimensional lattice. Though in the first instance a model of a lattice gas, it is sufficiently general to have served as the basis to model a wide variety of phenomena. That, as well as substantial progress made in analysing its stationary behaviour, including the locations and nature of phase transitions, have led to it becoming a paradigmatic model of an exactly solvable nonequilibrium system. Recently an exact solution for the dynamics found a somewhat enigmatic transition, which has not been well understood. This thesis is an attempt to verify and better understand the nature of that dynamical transition, including its relation, if any, to the static phase transitions. I begin in Chapter 2 by reviewing known results for the ASEP, in particular the totally asymmetric variant (TASEP), driven at the boundaries. I present the exact dynamical transition as it was first derived, and a reduced description of the dynamics known as domain wall theory (DWT), which locates the transition at a different place. In Chapter 3, I investigate solutions of a nonlinear PDE that constitutes a mean-field, continuum approximation of the ASEP, namely the Burgers equation, and find that a similar dynamical transition occurs there at the same place as predicted by DWT but in disagreement with the exact result. Next, in Chapter 4 I report on efforts to observe and measure the dynamical transition through Monte Carlo simulation. No directly obvious physical manifestation of the transition was observed. The relaxation of three different observables was measured and found to agree well with each other but only slightly better with the exact transition than with DWT. In Chapter 5 I apply a numerical renormalisation scheme known as the Density Matrix Renormalisation Group (DMRG) method and find that it confirms the exact dynamical transition, ruling out the behaviour predicted by DWT. Finally in Chapter 6 I demonstrate that a perturbative calculation, involving the crossing of eigenvalues, allows us to rederive the location of the dynamical transition found exactly, thereby offering some insight into the nature of the transition.
Differences in Media Preference Mediate the Link Between Personality and Political Orientation

Research has consistently demonstrated that political liberalism is predicted by the personality trait Openness to Experience and conservatism by trait Conscientiousness. Less well studied, however, is how trait personality influences political orientation. The present study investigated whether differences in media preference might mediate the links between personality and political orientation. Participants completed measures of Big Five personality, media preferences, and political orientation. Results revealed that increased preferences for Dark/Alternative and Aesthetic/Musical media genres, as well as decreased preferences for Communal/Popular media genres, mediated the association between Openness to Experience and liberalism. In contrast, greater preferences for Communal/Popular and Thrilling/Action genres, as well as lower preferences for Dark/Alternative and Aesthetic/Musical genres mediated the link between Conscientiousness and conservatism.
Detection and structural characterization of insulin prefibrilar oligomers using surface enhanced Raman spectroscopy

In vitro fibril formation typically exhibits a lag phase followed by a rapid elongation phase. Soluble prefibrilar oligomers form as multiple assembly states occur during the lag phase and, after forming a nucleus, rapidly propagate into amyloid aggregates and fibrils. The structure and morphology of amyloid fibrils have been extensively characterized over the last decades, while little is known about the structural organization of the prefibrilar oligomers or their multiple assembly states. The main difficulty in structural characterization of prefibrilar aggregates is their low concentration (pmolar) and their continual reactive conversion. Herein we overcome these difficulties by utilizing Surface‐Enhanced Raman Spectroscopy (SERS) with a model amyloid peptide, insulin. SERS is a powerful analytic tool that is able to provide detection of small molecules down to a single‐molecule level. Using SERS we found that during the 3 lag phase before the onset of insulin fibril formation, the amount of insulin oligomers increased more than twice after the first hour of incubation under fibrillation conditions (pH 1.6, 65°C) and then slowly decreased with time. The latter finding is kinetically linked to the conversion of the prefibrilar oligomers into fibril species. This study provides valuable new information about the time‐dependent structural organization of insulin oligomers and demonstrates the power and potential of SERS for detection and structural characterization of biological specimens present at low concentrations. © 2013 American Institute of Chemical Engineers Biotechnol. Prog. , 30:488–495, 2014