Miracle-dz/UniFAR-FTUs huggingface dataset:
Donepezil Adherence, Persistence and Time to First Discontinuation in a Three-Year Follow-Up of Older People

Background: Donepezil is indicated for the management of mild to moderate dementia, particularly in Alzheimer's disease. Several studies have described low adherence rates with donepezil. Aim: To examine and measure donepezil adherence, persistence and time to first discontinuation in older New Zealanders. Methods: An inception cohort of 1,999 new users of donepezil, aged 65 years or older, were identified from the Pharmaceutical Collections and National Minimum Dataset from 1 November 2010 to 31 December 2013. Kaplan-Meier curves and Cox regression analysis were used to estimate the cumulative probability and risk of time to first discontinuation of donepezil therapy. Results: The mean age of the cohort was 79.5 ± 6.4 years and included 42.7% females. Adherence was high (89.0%), while the proportion of donepezil dispensings (81.0-32.5%) declined between 6 and 36 months. Persistence between the 1st and 6th dispensing visit decreased by 19.0%, and 11.0% of the total cohort had a gap of 31 days or more. The adjusted risk of time to first discontinuation in the non-adherent group was 2.2 times (95% CI 1.9-2.6) that of the adherent group. Conclusions: The non-adherent new donepezil users, on average, discontinued faster than the adherent group. Time to first discontinuation in this study was higher compared to discontinuation rates observed in clinical trials.
MANAGERIAL JUDGEMENT AND RISK ASSESSMENT IN STRATEGIG INVESTMENT DECISIONS (SIDs)

The theoretical definition of risk applies where possible outcomes are known and the probability of those outcomes can be estimated. Risk analysis techniques therefore focus on the effect of risk. Several surveys indicate that these techniques are normally complemented or dominated by subjective or intuitive assessments of risk which has prompted a debate over a possible theory-practice gap. When an alternative theoretical perspective of decision-making under uncertainty is adopted, managerial cognition of 'risk' embraces human information processing capabilities, group dynamics and consensus-building. This approach encompasses managerial attempts to recognise unpredictable events and to isolate their causes. Whether risk is seen from a cause or effect perspective may be gauged by examining empirical, especially field-based studies which suggest a theory-theory gap exists. Emergence of this gap can be reconciled within the different stages of the strategic investment decision (SID) process. An emphasis on the cause of risk requires management judgements at lower levels in an organisation, at the project generation, business case and early screening stages, to be of fundamental importance. The subsequent effects of risk at the analysis and evaluation stage provide possibly complementary but secondary considerations for the SID. Given this increased emphasis on the causes of risk, future research possibilities are outlined in the concluding section. Correspondence details: Prof. Elaine P Harris De Montfort University The Gateway Leicester LE1 9 BH Phone: 0116 257 7211 Fax: 0116 251 7548 E-mail: eharris@dmu.ac. uk
TOP2Ahigh is the phenotype of recurrence and metastasis whereas TOP2Aneg cells represent cancer stem cells in prostate cancer

Recurrence and metastasis are the main causes of death for prostate cancer patients and cancer stem cells (CSCs) are proposed to play important roles in cancer recurrence and metastasis. It is generally thought that genes upregulated in recurrent/metastatic disease are likely biomarkers of CSCs. Hence we analyzed multiple microarray datasets on prostate tumor tissues to identify upregulated genes associated with cancer recurrence/metastasis, and tried to explore whether those genes were true biomarkers of prostate CSCs. Our results indicated that TOP2A was the most highly upregulated gene in recurrent/metastatic prostate cancer, and its high expression was positively correlated with poor prognosis in patients. Using a promoter reporter system, we unexpectedly discovered enrichment of CSCs in TOP2Aneg cells. Compared to TOP2Ahigh cells, TOP2Aneg cells formed spheres and tumors more efficiently, and became enriched in the presence of stresses. Analysis of cell divisions by time lapse imaging indicated that more slow-cycling cells were observed in TOP2Aneg cells while the proportion of abnormal divisions was higher in TOP2Ahigh cells. Our studies demonstrate that TOP2Ahigh is the phenotype of recurrence/metastasis but TOP2Aneg cells show slow cycling and have CSCs properties in prostate cancer, which has significant implications for prostate cancer therapy.
SUMO modification of a heterochromatin histone demethylase JMJD2A enables viral gene transactivation and viral replication

Small ubiquitin-like modifier (SUMO) modification of chromatin has profound effects on transcription regulation. By using Kaposi’s sarcoma associated herpesvirus (KSHV) as a model, we recently demonstrated that epigenetic modification of viral chromatin by SUMO-2/3 is involved in regulating gene expression and viral reactivation. However, how this modification orchestrates transcription reprogramming through targeting histone modifying enzymes remains largely unknown. Here we show that JMJD2A, the first identified Jumonji C domain-containing histone demethylase, is the histone demethylase responsible for SUMO-2/3 enrichment on the KSHV genome during viral reactivation. Using in vitro and in vivo SUMOylation assays, we found that JMJD2A is SUMOylated on lysine 471 by KSHV K-bZIP, a viral SUMO-2/3-specific E3 ligase, in a SUMO-interacting motif (SIM)-dependent manner. SUMOylation is required for stabilizing chromatin association and gene transactivation by JMJD2A. These finding suggest that SUMO-2/3 modification plays an essential role in the epigenetic regulatory function of JMJD2A. Consistently, hierarchical clustering analysis of RNA-seq data showed that a SUMO-deficient mutant of JMJD2A was more closely related to JMJD2A knockdown than to wild-type. Our previous report demonstrated that JMJD2A coated and maintained the “ready to activate” status of the viral genome. Consistent with our previous report, a SUMO-deficient mutant of JMJD2A reduced viral gene expression and virion production. Importantly, JMJD2A has been implicated as an oncogene in various cancers by regulating proliferation. We therefore further analyzed the role of SUMO modification of JMJD2A in regulating cell proliferation. Interestingly, the SUMO-deficient mutant of JMJD2A failed to rescue the proliferation defect of JMJD2A knockdown cells. Emerging specific inhibitors of JMJD2A have been generated for evaluation in cancer studies. Our results revealed that SUMO conjugation mediates an epigenetic regulatory function of JMJD2A and suggests that inhibiting JMJD2A SUMOylation may be a novel avenue for anti-cancer therapy.
Coordinated development of identified serotonergic neurons and their target ciliary cells in Helisoma trivolvis embryos

Embryonic neuron C1s (ENC1s) are bilateral serotonergic neurons that function as cilioexcitatory motor neurons in embryonic development of the pond snail, Helisoma trivolvis. Recent experiments demonstrated that these neurons stimulate cilia‐driven embryo rotation in response to hypoxia. In the present study, a comprehensive anatomic analysis of these cells and their target ciliary structures was done to address the following questions: (1) Does ENC1 have a morphology consistent with an oxygen‐sensitive sensory cell; (2) Is the development of ENC1's neurite outgrowth pathway coordinated with the development of its target effectors, the pedal and dorsolateral ciliary bands; and (3) What is the anatomic basis of ENC1–ciliary communication? By using an array of microscopic techniques on live and serotonin‐immunostained embryos, we found that each ENC1 possessed an apical dendrite that was capped with an integral dendritic knob penetrating the embryo surface. The dendritic knobs contained both microvilli and nonmotile cilia that suggested a sensory transduction role. Each ENC1 also possessed a descending projection, whose development was characterized by the rapid formation of the primary neurite pathway between stages E13 and E15, with the primary neurite of the right ENC1 developing in advance of its contralateral homologue. Secondary neurite branches formed between stages E15 and E30 in a spatiotemporal pattern that closely matched the development of the dorsolateral and pedal bands of cilia. Both dorsolateral and pedal ciliated cells formed basal processes that contacted ENC1 neurites. Finally, gap junction profiles were observed at neurite–neurite, neurite–ciliary cell, and ciliary cell–ciliary cell apposition sites, whereas putative chemical synaptic profiles were observed at neurite–neurite and neurite–ciliary cell apposition sites. J. Comp. Neurol. 457:313–325, 2003. © 2003 Wiley‐Liss, Inc.
Chromatographic and spectral studies of jetsam and archived ambergris

Abstract We describe determination of the dichloromethane-soluble components of 12 samples of the natural product, ambergris, using capillary gas chromatography–mass spectrometry (GC–MS). Ambergris is produced in vivo in about 1% of Sperm whales and is used in perfumery and for odour fixation. Whilst descriptions of ambergris chemistry appeared until about 40 years ago, few accounts of analyses of whole extracts of multiple samples of ambergris by GC–MS have been published before. As expected, our analyses revealed that the major component (up to 97% of the dichloromethane-soluble material) was ambrein, with co-occurring, variable proportions of steroids. Moreover, we report apparently for the first time, mass spectra and retention indices of derivatised ambrein. These data should now allow reliable, rapid confirmation of even small amounts of jetsam, archived museum and customs samples of ambergris and an assessment of ambergris ‘quality’.
Design of the C-Mod Advanced Outer Divertor

Operational requirements and research considerations make a high-temperature, toroidally continuous outer divertor an important aspect for future operation of the Alcator C-Mod tokamak. Leading edge melting of tiles, nonuniform heat loads, large electromagnetic forces, and localized impurity sources limit the performance of bulk plasmas. These issues can be addressed by the installation of a well-aligned, toroidally continuous outer divertor. In addition, future proposed long pulse operation of C-Mod will cause the temperature of the outer divertor to reach bulk temperatures as high as 500-600°C. This future operational requirement combined with the strong temperature dependence of plasma surface interactions (especially fuel retention), makes a controllable, high-temperature outer divertor desirable and necessary. The design and development of the C-Mod Advanced Outer Divertor (AOD) is discussed.
Keratinocyte growth factor (KGF) delays the onset of collagen-induced arthritis

Background: Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor family. KGF protects the oral and intestinal mucosa against damage induced by irradiation or chemotherapy. Previous studies have found the expression of KGF in chondrocytes and suggested that KGF promotes the wound healing process in injured cartilage. KGF also has important effects on the immune system such as the regeneration of thymus tissue and the formation of regulatory T cells (Treg) in the periphery. Aim: Here we investigated the effect of KGF on collagen type II induced arthritis (CIA) and anti-collagen antibody induced arthritis (CAIA) in order to discriminate between immunoregulatory effect and direct protective effect on chondrocytes. Methods: CIA was induced by immunization with CII and CAIA by treatment of mice with a cocktail of four different anti-CII antibodies. The effect of KGF on the thymus and spleen was analyzed by FACS and by immunohistochemistry. Results: We have found that KGF treatment delayed the onset of CIA but had no effect on CAIA. Our results show that KGF treatment leads both to an outflow of naïve T cells from the thymus and to a statistically significant increase in the percentage of CD4+Foxp3+ Tregs in the periphery. Conclusions: We suggest that the effect of KGF on CIA depends on immunoregulatory mechanisms. KGF may delay the aging of the cellular immune system and thus improve the resilience of the immune system against autoimmune reactions.
Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat

Clinical worsening often occurs 1 to 2 days after an intracerebral hemorrhage. Extracellular matrix proteolysis by metalloproteinases, which attack the basal lamina and open the blood-brain barrier, may be one contributing factor. Matrix metalloproteinases and plasminogen activators are increased 16 to 24 hours after a bacterial collagenase-induced intracerebral hemorrhage, suggesting that agents that block metalloproteinases may reduce the brain swelling after hemorrhage. Therefore, we injected 0.2, 0.3, 0.4, or 0.5 units bacterial collagenase intracerebrally in rats to produce an intracerebral hemorrhage. Twenty-four hours later, brain tissue was removed for measurement of brain water and electrolytes. Proteases were assayed by zymography. Treatment with a matrix metalloproteinase inhibitor, BB-1101, was begun 6 hours after the collagenase lesion, when the hematomas were formed and the secondary edema was increasing. Bacterial collagenase caused a dose-dependent hematoma at the injection site with secondary brain edema in both posterior regions. The lower bacterial collagenase doses (0.2 and 0.3 units) mainly caused brain edema in the tissue around the injection site, whereas the higher doses (0.4 and 0.5 units) also affected the opposite hemisphere. Administration of BB-1101 significantly reduced the brain water and sodium contents in regions away from the injection site in rats with 0.4 unit lesions (p < 0.05). Zymography showed an increase in 92-kDa type IV collagenase and urokinase-type plasminogen activator at 24 hours. Inhibitors of proteolytic cascade enzymes may be useful in treatment of secondary brain edema in intracerebral hemorrhage.
A Pepducin Derived from the Third Intracellular Loop of FPR2 Is a Partial Agonist for Direct Activation of This Receptor in Neutrophils But a Full Agonist for Cross-Talk Triggered Reactivation of FPR2

We recently described a novel receptor cross-talk mechanism in neutrophils, unique in that the signals generated by the PAF receptor (PAFR) and the ATP receptor (P2Y2R) transfer formyl peptide receptor 1 (FPR1) from a desensitized (non-signaling) state back to an actively signaling state (Forsman H et al., PLoS One, 8:e60169, 2013; Önnheim K, et al., Exp Cell Res, 323∶209, 2014). In addition to the G-protein coupled FPR1, neutrophils also express the closely related receptor FPR2. In this study we used an FPR2 specific pepducin, proposed to work as an allosteric modulator at the cytosolic signaling interface, to determine whether the cross-talk pathway is utilized also by FPR2. The pepducin used contains a fatty acid linked to a peptide sequence derived from the third intracellular loop of FPR2, and it activates as well as desensensitizes this receptor. We now show that neutrophils desensitized with the FPR2-specific pepducin display increased cellular responses to stimulation with PAF or ATP. The secondary PAF/ATP induced response was sensitive to FPR2-specific inhibitors, disclosing a receptor cross-talk mechanism underlying FPR2 reactivation. The pepducin induced an activity in naïve cells similar to that of a conventional FPR2 agonist, but with lower potency (partial efficacy), meaning that the pepducin is a partial agonist. The PAF- or ATP-induced reactivation was, however, much more pronounced when neutrophils had been desensitized to the pepducin as compared to cells desensitized to conventional agonists. The pepducin should thus in this respect be classified as a full agonist. In summary, we demonstrate that desensitized FPR2 can be transferred back to an actively signaling state by receptor cross-talk signals generated through PAFR and P2Y2R, and the difference in agonist potency with respect to pepducin-induced direct receptor activation and cross-talk reactivation of FPR2 puts the concept of functional selectivity in focus.
Bayesian Analysis of Parental Drinking Motives and Children's Adjustment

OF DISSERTATION BAYESIAN ANALYSIS OF PARENTAL DRINKING MOTIVES AND CHILDREN’S ADJUSTMENT Harm reduction strategies can mitigate against some of the deleterious effects of alcohol on families. These strategies are most feasible and cost-effective when they can be targeted at those who are most at risk. Previous studies examining the relation between parents’ alcohol use and their children’s psychological adjustment have failed to consider important contextual questions such as drinking motives. The current investigation set out to identify the extent to which parents’ drinking motives predict internalizing and externalizing psychopathology in their children. The investigation consisted of cross sectional analysis of parents’ drinking motives and their children’s adjustment using data from 154 families recruited from the local community. Utilizing Bayesian data analytic techniques, we examined the role of parents’ drinking motives along with possible mediating variables including familial conflict, parental depression, and parenting style. Results showed that maternal social drinking motives were better predictors of children’s maladjustment than either coping or enhancement drinking motives. Unexpectedly, maternal enhancement drinking motives were associated with fewer adjustment problems. Maternal enhancement drinking motives also predicted higher levels of collaborative conflict resolution and lower levels of parental depression, both of which were associated with reduced levels of children’s externalizing problems. Paternal alcohol consumption and drinking motives were not associated with children’s internalizing or externalizing problems. Clinical implications and directions for future research are discussed.
Enhanced Photovoltaic Properties of Bulk Heterojunction Organic Photovoltaic Devices by an Addition of a Low Band Gap Conjugated Polymer

In this study, we fabricated organic photovoltaics (OPVs) by introducing the polymer additive HTh6BT into the photoactive layer of a poly(3-hexylthiophene):phenyl-C61-butyric acid methyl ester (P3HT:PCBM) system. The HTh6BT had a relatively low band gap energy of 1.65 eV and a molecular and crystalline structure similar to that of P3HT. In the photoactive layer, the HTh6BT and P3HT can both act as donors. In such parallel-type bulk heterojunctions, each donor can form excitons and generate charges while being separated from the donor/acceptor interface. Changes in the photovoltaic property of the OPV device by the addition of HTh6BT were evaluated, and the optical characteristics of the photoactive layer, as well as the surface morphology, polymer ordering, and crystallinity of the P3HT:PCBM film were analyzed. Compared to a device without HTh6BT, all short-circuit current densities, open-circuit voltages, and fill factors were enhanced, leading to the enhancement of the power conversion efficiency by 36%.
Learning Noun-Modifier Semantic Relations with Corpus-based and WordNet-based Features

We study the performance of two representations of word meaning in learning noun-modifier semantic relations. One representation is based on lexical resources, in particular WordNet, the other - on a corpus. We experimented with decision trees, instance-based learning and Support Vector Machines. All these methods work well in this learning task. We report high precision, recall and F-score, and small variation in performance across several 10-fold cross-validation runs. The corpus-based method has the advantage of working with data without word-sense annotations and performs well over the baseline. The WordNet-based method, requiring word-sense annotated data, has higher precision.
Survival of Listeria monocytogenes in milk during high-temperature, short-time pasteurization

Milk from cows inoculated with Listeria monocytogenes was pooled for 2 to 4 days and then heated at 71.7 to 73.9 degrees C for 16.4 s or at 76.4 to 77.8 degrees C for 15.4 s in a high-temperature, short-time plate heat exchanger pasteurization unit. L. monocytogenes was isolated from milk after heat treatment in six of nine pasteurization trials done at 71.7 to 73.9 degrees C and in none of three trials done at 76.4 to 77.8 degrees C. An average of 1.5 to 9.2 L. monocytogenes cells was seen in each milk polymorphonuclear leukocyte before heat treatment in 11 of 12 pasteurization trials. Noticeable degradation of leukocytes with intracellular listeria was detected in unpasteurized milk after 3 days of storage at 4 degrees C, and by 4 days of storage leukocytes had deteriorated to cellular debris, suggesting that holding unpasteurized milk refrigerated for 4 or more days would eliminate a protective effect leukocytes may provide for increasing heat resistance of L. monocytogenes. Results indicate that under the conditions of this study, L. monocytogenes can survive the minimum high-temperature, short-time treatment (71.7 degrees C, 15 s) required by the U.S. Food and Drug Administration for pasteurizing milk.
Effects of Literacy in Early Visual and Occipitotemporal Areas of Chinese and French Readers

How does reading expertise change the visual system? Here, we explored whether the visual system could develop dedicated perceptual mechanisms in early and intermediate visual cortex under the pressure for fast processing that is particularly strong in reading. We compared fMRI activations in Chinese participants with limited knowledge of French and in French participants with no knowledge of Chinese, exploiting these doubly dissociated reading skills as a tool to study the neural correlates of visual expertise. All participants viewed the same stimuli: words in both languages and matched visual controls, presented at a fast rate comparable with fluent reading. In the Visual Word Form Area, all participants showed enhanced responses to their known scripts. However, group differences were found in occipital cortex. In French readers reading French, activations were enhanced in left-hemisphere visual area V1, with the strongest differences between French words and their controls found at the central and horizontal meridian representations. Chinese participants, who were not expert French readers, did not show these early visual activations. In contrast, Chinese readers reading Chinese showed enhanced activations in intermediate visual areas V3v/hV4, absent in French participants. Together with our previous findings [Szwed, M. , Dehaene, S. , Kleinschmidt, A. , Eger, E. , Valabregue, R. , Amadon, A. , et al. Specialization for written words over objects in the visual cortex. Neuroimage, 56, 330–344, 2011], our results suggest that the effects of extensive practice can be found at the lowest levels of the visual system. They also reveal their cross-script variability: Alphabetic reading involves enhanced engagement of central and right meridian V1 representations that are particularly used in left-to-right reading, whereas Chinese characters put greater emphasis on intermediate visual areas.