Miracle-dz/UniFAR-FTUs huggingface dataset:
A novel TALE nuclease scaffold enables high genome editing activity in combination with low toxicity

Sequence-specific nucleases represent valuable tools for precision genome engineering. Traditionally, zinc-finger nucleases (ZFNs) and meganucleases have been used to specifically edit complex genomes. Recently, the DNA binding domains of transcription activator-like effectors (TALEs) from the bacterial pathogen Xanthomonas have been harnessed to direct nuclease domains to desired genomic loci. In this study, we tested a panel of truncation variants based on the TALE protein AvrBs4 to identify TALE nucleases (TALENs) with high DNA cleavage activity. The most favorable parameters for efficient DNA cleavage were determined in vitro and in cellular reporter assays. TALENs were designed to disrupt an EGFP marker gene and the human loci CCR5 and IL2RG. Gene editing was achieved in up to 45% of transfected cells. A side-by-side comparison with ZFNs showed similar gene disruption activities by TALENs but significantly reduced nuclease-associated cytotoxicities. Moreover, the CCR5-specific TALEN revealed only minimal off-target activity at the CCR2 locus as compared to the corresponding ZFN, suggesting that the TALEN platform enables the design of nucleases with single-nucleotide specificity. The combination of high nuclease activity with reduced cytotoxicity and the simple design process marks TALENs as a key technology platform for targeted modifications of complex genomes.
Abstract 628: Pan-Bcl-2 inhibitor, GX15-070 (Obatoclax), decreases human T regulatory lymphocytes while preserving effector T Lymphocytes: A rationale for its use in combination immunotherapy

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Bcl-2 inhibitors are currently being evaluated in clinical studies for treatment of patients with solid tumors and hematopoietic malignancies. In this study we explored the potential for combining the pan-Bcl-2 inhibitor GX15-070 (GX15; obatoclax) with immunotherapeutic modalities. We evaluated the in vitro effects of GX15 on human T-cell subsets obtained from PBMCs in terms of activation, memory, and suppressive function. Our results indicated that in healthy-donor PBMCs, mature-activated T cells were more resistant to GX15 than early-activated T cells, and that GX15 preserved memory but not non-memory T-cell populations. Furthermore, GX15 increased the apoptosis of regulatory T cells (Tregs), profoundly down-regulated FOXP3 and CTLA-4 in a dose-dependent manner, and decreased their suppressive function. Treating PBMCs obtained from ovarian cancer patients with GX15 also resulted in increased CD8+:Treg and CD4+:Treg ratios. These results support preclinical studies in which mice vaccinated before treatment with GX15 showed the greatest reduction in metastatic lung tumors as a result of increased apoptotic resistance of mature CD8+ T cells and decreased Treg function brought about by GX15. Taken together, these findings suggest that when a Bcl-2 inhibitor is combined with active immunotherapy in humans, such as the use of a vaccine or immune checkpoint inhibitor, immunotherapy should precede administration of the Bcl-2 inhibitor to allow T cells to become mature, and thus resistant to the cytotoxic effects of the Bcl-2 inhibitor. Citation Format: Peter S. Kim, Caroline Jochems, Italia Grenga, Renee N. Donahue, Kwong Y. Tsang, James L. Gulley, Jeffrey Schlom, Benedetto Farsaci. Pan-Bcl-2 inhibitor, GX15-070 (Obatoclax), decreases human T regulatory lymphocytes while preserving effector T Lymphocytes: A rationale for its use in combination immunotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 628. doi:10.1158/1538-7445.AM2014-628
Evolving autonomous agent control in the Xpilot environment

Interactive combat games are useful as test-beds for learning systems employing evolutionary computation. Of particular value are games that can be modified to accommodate differing levels of complexity. In this paper, the authors presented the use of Xpilot as a learning environment that can be used to evolve primitive reactive behaviors, yet can be complex enough to require combat strategies and team cooperation. In addition, this environment was used with a genetic algorithm to learn the weights for an artificial neural network controller that provides both offensive and defensive reactive control for an autonomous agent.
Uso de inventários comportamentais para a avaliação socioemocional em idade pré-escolar

The last 30 years are ruled by an increased interest in the assessment of the social-emotional development/functioning of preschool children. However, the assessment of this younger population, with specific characteristics (example, restricted vocabulary), requires the use of a distinct approach from the one used with school age children/adults. In this context, the use of rating scales has assumed a prominent role. The present paper aims to highlight the importance of rating scales as a measure of preschoolers social-emotional functioning. The critical review indicates that, despite several advantages (example, brevity and cost efficiency), there are also some limitations related to this kind of assessment instrument (example, bias of response), and recommendations for its efficient use are pointed out.
Consumption-Income Sensitivity and Portfolio Choice

Contrary to the predictions of traditional life-cycle models, household consumption is excessively sensitive to current income. Similarly, weak evidence of income hedging runs against standard portfolio theory. We link these two puzzles by modifying the theoretical framework of Viceira (2001) to study how consumption-income sensitivities generated by income in the utility function affect households' portfolio choices. Empirically, we find that consumption-income sensitivities affect asset allocation through the income hedging channel. In particular, we show that the interaction between consumption-income sensitivity and the correlation of income growth to stock market returns is an important explanatory variable for households' stock market holdings. Received October 20, 2016; editorial decision April 25, 2018 by Editor Wayne Ferson.
Self-mutilation in young rats after dorsal rhizotomy.

OBJECTIVES The aim of the study was to describe the development of self-mutilation after extensive dorsal rhizotomy of the brachial plexus performed during early ontogeny in rats. SETTINGS AND DESIGN The rhizotomy was performed in three groups of rats according to the central nervous system maturation: infant, young, and adult. After the surgery the occurrence of self-mutilation behavior was compared. Rats from the infant group and non-mutilating deafferentated rats from the adult group underwent extracellular recordings from intralaminar thalamic neurons. Interspikes intervals of the records were compared by means of chaodynamic methods. RESULTS In the infant group self-mutilation did not develop at all. Among the young group self-mutilation developed in 40% of rats and consisted of superficial wounds in all cases. In adult self-mutilation appeared in 80% rats and consisted of both superficial wounds (75%) and amputation (25%). In the newborn group and the deafferentated adult group without any signs of self-mutilation means of the parameters were not significantly different and were significantly lower than those of intact adult rats. MAIN FINDINGS 1. Self-mutilation does not develop after the rhizotomy in the infant rats. 2. Neurons behave in chaotic way in adult as well as in young animals. 3. Chaodynamic parameters do not differ between infant and adult rats without any signs of self-mutilation. CONCLUSIONS The results suggest that development of self-mutilation behavior in rats strongly depends on the ontogenetical period of nervous system injury, and that mature nervous system is required for the development of described pathological behavior.
Independent and inverse association of healthcare utilisation with physical activity in older adults with multiple chronic conditions

Objective In this study, whether physical activity is independently associated with direct healthcare costs in community-dwelling older adults with multiple chronic conditions was examined. Design Cross-sectional analysis Setting Research laboratory Participants 299 community-dwelling men and women volunteers aged 65 years and older with chronic conditions. Intervention None. Main outcome measures Primary dependent variable was direct healthcare costs incurred in the previous 3 months. Participants completed the Health Resource Utilisation (HRU) questionnaire. To estimate HRU, direct costs in the previous 3 months were calculated using the three-party payer perspective of the British Columbia Ministry of Health, deemed representative of the Canadian healthcare system costs. For medications, the Retail Pharmacy Dispensed prescription cost tables were used. Primary independent variables were (1) self-report current level of physical activity as assessed by the Physical Activity Scale for Individuals with Physical Disabilities (PASIPD) and (2) general balance and mobility as assessed by the National Institute on Aging Balance Scale. Results The mean number of chronic conditions per participant was six. Current level of physical activity was independently and inversely associated with HRU. Age, sex, number of chronic conditions, global cognitive function, body mass index, and general balance and mobility together accounted for 24.3% of the total variance. Adding the PASIPD score resulted in an R2 change of 3.3% and significantly improved the model. The total variance accounted by the final model was 27.6%. Conclusions Physical activity promotion may reduce healthcare costs in older adults with chronic conditions.
Global gene expression profile of Saccharomyces cerevisiae induced by dictamnine

Dictamnine, a natural plant product, has been reported to have antimicrobial activity against bacteria and fungi; however, the dictamnine response mechanisms of microorganisms are still poorly understood. We have shown that dictamnine has antimicrobial activities against the model fungus Saccharomyces cerevisiae, with a minimum inhibitory concentration (MIC) value of 64 µg/ml. Commercial oligonucleotide microarrays were used to determine the global transcriptional response of S. cerevisiae triggered by treatment with dictamnine. We interpreted our microarray data using the hierarchical clustering tool, T‐profiler. Several major transcriptional responses were induced by dictamnine. The first was the induced environmental stress response, mainly under the control of the Msn2p and Msn4p transcription factors, and the repressed environmental stress response in genes containing the PAC (RNA polymerase A and C box) and rRPE (ribosomal RNA processing element) motifs. The second was the Upc2p‐mediated response involved in lipid biosynthesis. The third comprised the PDR3‐ and RPN4‐mediated responses involved in multidrug resistance (MDR). Finally, the TBP‐mediated response was induced with dictamnine treatment. TBP is an essential general transcription factor involved in directing the transcription of genes. Quantitative real‐time RT–PCR was performed on selected genes to verify the microarray results. Furthermore, morphological transitions during dictamnine exposure to S. cerevisiae L1190 (MATa/α) were examined, using confocal laser microscopy. Copyright © 2008 John Wiley & Sons, Ltd.
All-Optical Switching in Rubidium Vapor

We report on an all-optical switch that operates at low light levels. It consists of laser beams counterpropagating through a warm rubidium vapor that induce an off-axis optical pattern. A switching laser beam causes this pattern to rotate even when the power in the switching beam is much lower than the power in the pattern. The observed switching energy density is very low, suggesting that the switch might operate at the single-photon level with system optimization. This approach opens the possibility of realizing a single-photon switch for quantum information networks and for improving transparent optical telecommunication networks.
Third-Generation &bgr;-Blockers Stimulate Nitric Oxide Release From Endothelial Cells Through ATP Efflux: A Novel Mechanism for Antihypertensive Action

Background—Nebivolol and carvedilol are third-generation &bgr;-adrenoreceptor antagonists, which unlike classic &bgr;-blockers, have additional endothelium-dependent vasodilating properties specifically related to microcirculation by a molecular mechanism that still remains unclear. We hypothesized that nebivolol and carvedilol stimulate NO release from microvascular endothelial cells by extracellular ATP, which is a well-established potent autocrine and paracrine signaling factor modulating a variety of cellular functions through the activation of P2-purinoceptors. Methods and Results—Contraction and relaxation of renal glomerular vasculature were measured by determination of intracapillary volume with [3H]-inulin. Biologically active NO was measured with highly sensitive porphyrinic NO microsensors in a single glomerular endothelial cell (GEC). Extracellular ATP was measured by a luciferin-luciferase assay. Enzymatic degradation of extracellular ATP by apyrase and blockade of P2Y-purinoceptors by suramin or reactive blue 2 inhibited both &bgr;-blocker–induced glomerular vasorelaxations and &bgr;-blocker–stimulated NO release from GECs. Both &bgr;-blocker–induced vasorelaxations were in the micromolar concentration range identical to that required for the &bgr;-blocker stimulation of ATP and NO release from GECs. The maximum of NO release for nebivolol and carvedilol was very similar (188±14 and 226±17, respectively). Blockade of ATP release by a mechanosensitive ion channel blocker, Gd3+, inhibited the &bgr;-blocker–dependent release of ATP and NO from GECs. Conclusions—These results demonstrate for the first time that nebivolol and carvedilol induce relaxation of renal glomerular microvasculature through ATP efflux with consequent stimulation of P2Y-purinoceptor–mediated NO release from GECs.
Where there is a WIL there is a way

While work‐integrated learning (WIL) is seen as a way to address the call for improved ‘employment readiness’ and generic skills of graduates, it has been stated that WIL programs need to be ‘well managed and structured’ and ‘well integrated’. To provide such structure and integration a Professional Development (PD) Program was developed to assist students who would undertake a WIL internship as part of their business degree. This paper details evidence of the impact of the PD Program for first year students compared to those undertaking a conventional orientation process. The preliminary evidence demonstrate that structure and integration of the PD Program has had positive effects in terms of generic skills, satisfaction and self‐efficacy.
Routine fiberoptic endoscopic evaluation of swallowing following prolonged intubation: implications for management.

HYPOTHESIS Fiberoptic endoscopic evaluation of swallowing (FEES) will identify patients who are at high risk for pulmonary aspiration due to swallowing dysfunction after prolonged intubation. Based on the results of FEES, dietary recommendations can be made to decrease the incidence of aspiration after prolonged intubation. DESIGN Patients who were intubated for at least 48 hours were evaluated for swallowing dysfunction by bedside FEES within 48 hours of extubation. Differences in potential risk factors between aspirators and nonaspirators were analyzed. Dietary recommendations were made and patients were followed up for signs of clinically significant aspiration. SETTING Community teaching hospital. PATIENTS Fifty-one consecutive patients with no previously documented swallowing disorder who required a minimum of 48 hours of intubation for mechanical ventilation. INTERVENTIONS Fiberoptic endoscopic evaluation of swallowing was performed by a speech pathologist. Initial diet orders were determined by results of the swallowing study. MAIN OUTCOME MEASURES Incidence of swallowing dysfunction following prolonged intubation and incidence of clinically significant aspiration following initiation of oral feeding. RESULTS Incidence of swallowing dysfunction was 56% (27/48); 12 (25%) of 48 patients were silent aspirators. In comparing aspirators with nonaspirators, no significant differences in potential risk factors or comorbidities were seen. Nineteen (70%) of the 27 patients aspirated with thin-consistency test liquids, and the other 8 (30%) with puree consistency. No patients in this study group developed a clinically significant aspiration following initiation of appropriately modified diets. CONCLUSIONS Fiberoptic endoscopic evaluation of swallowing identified swallowing dysfunction in more than 50% of patients intubated for longer than 48 hours, many of whom are silent aspirators. Dietary recommendations based on FEES results prevented clinically significant aspiration.
GPU-optimized efficient quad-tree based progressive multiresolution model for interactive large scale terrain rendering

This paper presents new effective method for real-time terrain triangulation and visualization. The method utilizes compact progressive terrain representation which is constructed at preprocess stage and requires a very low memory expense. This representation allows easily LOD extraction at runtime. In contrast to previous works our quadtree-based triangulation is not restricted such that neighboring regions must differ by at most one level in LOD hierarchy. This allows constructing more adaptive triangulation. The method performs LOD selection on per-block basis and thus it is not CPU-consuming and fully exploits power of modern graphics hardware. Patch triangulations are constructed only once the first time the patch is needed and cached in fast video memory in optimized form in order to achieve highest rendering performance. The method is driven by the user-defined screen space error and provides guaranteed surface e-approximation. The algorithm supports morphing of both geometry and texture (the last is not usually discussed) which hides popping artifacts related with LOD change. We also discuss some system-level aspects such as multithreaded asynchronous implementation of the proposed algorithm, video-memory allocation control, camera position prediction and speculative data prefetch. The proposed method can be easily extended to allow terrain compression.
On the Occasion of World Cancer Day 2015; the Possibility of Cancer Prevention or Treatment with Antioxidants: The Ongoing Cancer Prevention Researches

On February, 2014 World Cancer Day (WCD) was established to raise alertness of cancer and to encourage its prevention, detection, and treatment. In fact, WCD is celebrated every year on the 4th of February all over the world to commemorate all the accomplishments of the WHO. In this paper, we aimed to present the scientific evidence for the role of antioxidants in cancer. Damage to cells by reactive oxygen species, especially the damage to DNA, has been found to play a crucial role in the development of cancer. Exogenous antioxidants can prevent free radical damage associated with cancer development. However, whether or not taking dietary antioxidants can prevent or reduce the risk of developing cancer in humans is not clear. Some researchers have suggested that antioxidants counteract with drugs or toxins, which induce oxidative stress and hence prevent damage to cells or body organs.
Lactose Intolerance in Active Crohn's Disease: Clinical Value of Duodenal Lactase Analysis

Background Patients with active Crohn's disease (CD) often report having abdominal symptoms after ingestion of milk products, but the pathomechanism for lactose malabsorption seems to be complex. Goals To investigate the prevalence of clinical milk intolerance and to objectify symptoms with hydrogen (H 2 ) breath testing, analysis of lactase protein, and enzyme activity in the duodenal mucosa in patients with CD and in healthy controls. Study In 49 patients with CD and 24 controls, H 2 breath testing was performed. All individuals underwent endoscopy of the upper gastrointestinal tract, in which multiple pinch samples were taken from the distal duodenum. Lactase activity was measured using the method of Dahlquist. The lactase protein expression was analyzed by gel electrophoresis using the monoclonal antibody mlac 10 and by immunochemistry using the monoclonal antibody mlac 4. Results Prevalence of milk intolerance in healthy controls was 16.6% versus 46.9% in patients with CD, with a high frequency (83.3%) in patients with active disease (CD activity index >150). Milk intolerance was correlated to the duration of inflammatory bowel disease (p = 0.023) but not to the location or previous bowel resection. Hydrogen breath testing had a moderate sensitivity in detecting lactose maldigestion (70.4%) and a high specificity (95.6%). Duodenal lactase levels were also correlated to disease activity, whereas correlations to clinical symptoms remained poor. Patients with milk intolerance had a significantly reduced bone density at the lumbar spine (z-score, −1.33 ± 0.92 vs. −0.19 ± 0.95 [mean ± SD];p = 0.002) Conclusions Milk intolerance is a frequent problem in active CD, which can be objectified accurately by H 2 lactose breath testing. Decreased lactase levels in the duodenal mucosa may be found during an acute flare but are not the predominant cause of milk intolerance in CD.
Research, part of a Special Feature on Empirical based agent-based modeling Agent-based Analysis of Agricultural Policies: an Illustration of the Agricultural Policy Simulator AgriPoliS, its Adaptation and Behavior

This paper combines agent-based modeling of structural change with agricultural policy analysis. Using the agent-based model AgriPoliS, we investigate the impact of a regime switch in agricultural policy on structural change under various framework conditions. Instead of first doing a sensitivity analysis to analyze the properties of our model and then examining the introduced policy in an isolated manner, we use a meta-modeling approach in combination with the statistical technique of Design of Experiments to systematically analyze the relationship between policy change and model assumptions regarding key determinants of structural change such as interest rates, managerial abilities, and technical change. As a result, we observe that the effects of policies are quite sensitive to the mentioned properties. We conclude that an isolated analysis of a policy regime switch would be of only minor value for policy advice given the ability of simulation models to examine various potential futures.