Miracle-dz/UniFAR-FTUs huggingface dataset:
Correlating Efficacy in Rodent Cognition Models with in Vivo 5-Hydroxytryptamine1A Receptor Occupancy by a Novel Antagonist, (R)-N-(2-Methyl-(4-indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl)-cyclohexane Carboxamide (WAY-101405)

5-Hydroxytryptamine (5-HT)1A receptors play an important role in multiple cognitive processes, and compelling evidence suggests that 5-HT1A antagonists can reverse cognitive impairment. We have examined the therapeutic potential of a potent (Ki = 1.1 nM), selective (>100-fold), orally bioavailable, silent 5-HT1A receptor antagonist (KB = 1.3 nM) (R)-N-(2-methyl-(4-indolyl-1-piperazinyl)-ethyl)-N-(2-pyridinyl)-cyclohexane carboxamide (WAY-101405). Oral administration of WAY-101405 was shown to be effective in multiple rodent models of learning and memory. In a novel object recognition paradigm, 1 mg/kg enhanced retention (memory) for previously learned information, and it was able to reverse the memory deficits induced by scopolamine. WAY-101405 (1 mg/kg) was also able to reverse scopolamine-induced deficits in a rat contextual fear conditioning model. In the Morris water maze, WAY-101405 (3 mg/kg) significantly improved learning in a paradigm of increasing task difficulty. In vivo microdialysis studies in the dorsal hippocampus of freely moving adult rats demonstrated that acute administration of WAY-101405 (10 mg/kg) increased extracellular acetylcholine levels. The selective radioligand [3H]WAY-100635, administered i.v. , was used for in vivo receptor occupancy studies, where WAY-101405 occupied 5-HT1A receptors in the rat cortex, with an ED50 value of 0.1 mg/kg p.o. Taken together, these studies demonstrate that WAY-101405 is a potent and selective, brain penetrant, orally bioavailable 5-HT1A receptor “silent” antagonist that is effective in preclinical memory paradigms at doses where approximately 90% of the postsynaptic 5-HT1A receptors are occupied. These results further support the rationale for use of this compound class in the treatment of cognitive dysfunction associated with psychiatric and neurological conditions.
Single-amino-acid substitutions within the signal sequence of yeast prepro-alpha-factor affect membrane translocation

We used a genetic approach to identify point mutations in the signal sequence of a secreted eucaryotic protein, yeast alpha-factor. Signal sequence mutants were obtained by selecting for cells that partially mistargeted into mitochondria a fusion protein consisting of the alpha-factor signal sequence fused to the mature portion of an imported mitochondrial protein (Cox IV). The mutations resulted in replacement of a residue in the hydrophobic core of the signal sequence with either a hydrophilic amino acid or a proline. After reassembly into an intact alpha-factor gene, the substitutions were found to decrease up to 50-fold the rate of translocation of prepro-alpha-factor across microsomal membranes in vitro. Two of three mutants tested produced lower steady-state levels of alpha-factor in intact yeast cells, although the magnitude of the effect was less than that in the cell-free system.
Deep brain stimulation for movement disorders

Deep brain stimulation is now considered a routine treatment option for selected patients with advanced Parkinson’s disease, primary segmental and generalised dystonia, and essential tremor. The neurosurgeon is responsi ble for the accurate and safe placement of the electrodes and the neurologist for the careful selection of patients and titration of medication against the effects of stimulation. A multidisciplinary team approach involving specialist nurses, neuropsychologists and neurophysiologists is required for a successful outcome. In this article we will summarise the key points in patient selection, provide an overview of the surgical technique, and discuss the beneficial and adverse outcomes that can occur.
The effects of feeding rations that differ in neutral detergent fiber and starch concentration within a day on production, feeding behavior, total-tract digestibility, and plasma metabolites and hormones in dairy cows.

Dairy cows exhibit a daily pattern of feed intake and milk synthesis, and feeding a single total mixed ration over the day may not synchronize ruminal fermentation, nutrient absorption, and milk synthesis. Our hypothesis was that feeding a high-fiber diet during the high-intake period of the day and a low-fiber diet during the low-intake overnight period would stabilize rumen fermentation, nutrient absorption, and the availability of nutrients for milk synthesis. Nine ruminally cannulated cows were used in a 3×3 Latin square design with 23-d periods. Diets were a control [CON; 33.3% neutral detergent fiber (NDF)], a low-fiber diet (LF; 29.6% NDF), and a high-fiber diet (HF; 34.8% NDF). The HF and LF diets were balanced to provide the same nutrient composition as the control diet when cows were fed a 7:3 ratio of HF:LF. Control cows were fed once daily at 0900h. Cows in the high/low treatment (H/L) were fed HF at 70% of daily offering at 0900h and LF at 30% of daily offering at 2200h; cows in the low/high (L/H) treatment were fed LF at 30% of daily offering at 0900h and HF at 70% of daily offering at 1300h. Dry matter intake was decreased 1.9kg/d by H/L compared with CON, but intake did not differ between H/L and L/H. The H/L and L/H treatments resulted in a large amount of feed consumed after each feeding, which shifted the daily patterns of starch and fiber intake. Treatments did not differ in total-tract digestibility. We detected no differences between CON and H/L for milk yield and composition. The H/L treatment unexpectedly tended to reduce milk and reduced milk fat yield compared with L/H, although L/H was expected to result in poorer rumen fermentation and decreased milk fat yield. Treatment did not affect milk fat concentrations of trans-10 C18:1, trans-11 C18:1, or de novo synthesized fatty acids, but H/L increased milk fat concentration of preformed fatty acids compared with CON (39.15 vs. 37.38% of FA, respectively). Treatment had no effect on plasma insulin or glucose at individual time points but did modify the phase and amplitude of the daily rhythms. Daily average plasma nonesterified fatty acids (NEFA) were decreased by H/L compared with CON and L/H, and H/L treatments decreased the amplitude of the daily rhythm of NEFA by 3.4 and 6. 7μEq/L compared with CON and L/H, respectively. The amplitude of the daily rhythm of plasma blood urea N was increased by more than 15% by H/L compared with CON and L/H. Feeding multiple rations over the day changed the daily pattern of starch and fiber intake and decreased daily intake without decreasing milk yield or body weight gain over the 23-d observation periods. Feeding a high-fiber diet during the high-intake period of the day and a low-fiber diet during the low-intake overnight period failed to show other benefits, likely because of the change in feeding behavior.
Nanocrystal Photodetector Technologies

Light detection is the underlying principle of many optoelectronic systems. For decades, semiconductors such as silicon carbide, silicon, indium gallium arsenide and germanium have dominated the photodetector industry. They can exhibit excellent photosensitivity but are limited by one or more aspect, for example high production cost, high temperature processing, flexible substrate incompatibility, limited spectral range or requiring cryogenic cooling for efficient operation. Recently lead sulphide (PbS) nanocrystals have emerged as one of the most promising new materials for photodetector fabrication. They offer several advantages including low cost manufacturing, solution processability, sizetunable spectral sensitivity, flexible substrate compatibility and have achieved figures of merit outperforming conventional photodetectors. We review the underlying concepts, breakthroughs and remaining challenges in PbS nanocrystal based photodetector technologies.
Dual Regulation of Myocardin Expression by Tumor Necrosis Factor-α in Vascular Smooth Muscle Cells

De-differentiation of vascular smooth muscle cells (VSMCs) plays a critical role in the development of atherosclerosis, a chronic inflammatory disease involving various cytokines such as tumor necrosis factor-α (TNFα). Myocardin is a co-factor of serum response factor (SRF) and is considered to be the master regulator of VSMC differentiation. It binds to SRF and regulates the expression of contractile proteins in VSMCs. Myocardin is also known to inhibit VSMC proliferation by inhibiting the NF-κB pathway, whereas TNFα is known to activate the NF-κB pathway in VSMCs. NF-κB activation has also been shown to inhibit myocardin expression and smooth muscle contractile marker genes. However, it is not definitively known whether TNFα regulates the expression and activity of myocardin in VSMCs. The current study aimed to investigate the role of TNFα in regulating myocardin and VSMC function. Our studies showed that TNFα down-regulated myocardin expression and activity in cultured VSMCs by activating the NF-κB pathway, resulting in decreased VSMC contractility and increased VSMC proliferation. Surprisingly, we also found that TNFα prevented myocardin mRNA degradation, and resulted in a further significant increase in myocardin expression and activity in differentiated VSMCs. Both the NF-κB and p44/42 MAPK pathways were involved in TNFα regulation of myocardin, which further increased the contractility of VSMCs. These differential effects of TNFα on myocardin seemingly depended on whether VSMCs were in a differentiated or de-differentiated state. Taken together, our results demonstrate that TNFα differentially regulates myocardin expression and activity, which may play a key role in regulating VSMC functions.
The effect of melatonin treatment regimen on mammary adenocarcinoma development in HER‐2/neu transgenic mice

The effect of various regimens of treatment with melatonin on the development of mammary tumors in HER2/neu transgenic mice was investigated. Female HER‐2/neu mice starting from the age of 2 months were kept under standard light/dark regimen and as given melatonin with tap water (20 mg/l) during the night time 5 times monthly (interrupted treatments) or constantly to natural death. Intact mice served as controls. Treatment with melatonin slowed down age‐related disturbances in estrous function most in the group exposed to interrupted treatment with the hormone. Constant treatment with melatonin decreased incidence and size of mammary adenocarcinomas, and incidence of lung metastases, compared to controls. The number of mice bearing 4 and more tumors was reduced in the group with constant melatonin treatment. Interrupted treatment with melatonin promote mammary carcinogenesis in HER‐2/neu transgenic mice. The data demonstrate the regimen‐dependent inhibitory effect of melatonin on the development of spontaneous mammary tumors in HER‐2/neu mice but not on overall survival with implication about the likely cause of the effect. Polycystic kidney disease is common in this transgenic line. Adverse effect of melatonin on the life span in our study may be unique to the transgenic model used and may not be relevant to the suppressive effect of melatonin in delay of mammary cancer. © 2002 Wiley‐Liss, Inc.
The affordance-matching hypothesis: how objects guide action understanding and prediction

Action understanding lies at the heart of social interaction. Prior research has often conceptualized this capacity in terms of a motoric matching of observed actions to an action in one’s motor repertoire, but has ignored the role of object information. In this manuscript, we set out an alternative conception of intention understanding, which places the role of objects as central to our observation and comprehension of the actions of others. We outline the current understanding of the interconnectedness of action and object knowledge, demonstrating how both rely heavily on the other. We then propose a novel framework, the affordance-matching hypothesis, which incorporates these findings into a simple model of action understanding, in which object knowledge—what an object is for and how it is used—can inform and constrain both action interpretation and prediction. We will review recent empirical evidence that supports such an object-based view of action understanding and we relate the affordance matching hypothesis to recent proposals that have re-conceptualized the role of mirror neurons in action understanding.
Multi-granularities approximate method for obtaining qualitative spatial relations

Qualitative spatial relations are widely used in spatial description logics, spatial ontologies and other applications. Efficient method to obtain qualitative spatial relations from traditional GIS has not been discussed in previous literatures. We give an efficient method for calculating qualitative spatial relations. We propose the multi-granularities approximate representation of GIS objects which requires less process time. Then some algorithms are proposed to calculate the spatial relations based on multi-granularities approximate region. The analysis and test result all show that our method supports complex and integrated spatial relations and require less process time than traditional spatial query.
Empirical study of industrial decision making for software modernizations

This paper describes the results of an empirical study focusing on software modernization decision making in software industry. 29 decision making experts were interviewed. The main aim was to gather versatile information about their views by posing 26 questions concerning decision making. Topics of interest of these questions included: decision makers, decision making process, used and needed methods and tools, confirmation of decisions, and decision criteria. Six important themes were identified and discussed: role of intuition, economical evaluation, confirmation of the decisions, group decision making, tool support, and success and limitations of the conducted empirical study. The most important findings include the following: use of intuition in decision making is polarized, economical evaluation is important and pursued but reliable estimation of benefits is hard fo achieve, decisions are seldom confirmed, group decision support aspects appear to be important, and tool support for expert judgment needs to be improved.
Managing Police Patrol Time: The Role of Supervisor Directives

Contemporary police practice advocates the importance of proactive policing activities. Proactive policing reforms emphasize self‐initiated tasks during unassigned patrol time and directed activities based on supervisor review of crime analysis and problem identification. Our study analyzes data from systematic social observations of police patrol officers to examine how officers spent their discretionary time. We find that, on average, over three quarters of a patrol officers’ shift is unassigned. During this time, officers primarily self‐initiate routine patrol, or back up other officers on calls to which they were not dispatched. Just 6 percent of unassigned time activities are directed by supervising officers, dispatchers, other officers or citizens. Moreover, directives provided by supervisors are vague, general in form, and do not operationalize problem‐oriented policing, community‐oriented policing, or proactive policing strategies. We conclude that first, a very significant proportion of patrol officer time is spent uncommitted that could be better utilized doing proactive, problem‐oriented policing activities, and second, supervisors need to provide patrol officers with much more detailed directives, based on sound crime analysis, to help capitalize on the under‐utilization of patrol officer time.
Entropy-Based Termination Criterion for Multiobjective Evolutionary Algorithms

Multiobjective evolutionary algorithms evolve a population of solutions through successive generations toward the Pareto-optimal front (POF). One of the most critical questions faced by the researchers and practitioners in this domain relates to the number of generations that may be sufficient for an algorithm to offer a good approximation of the POF for a given problem. Ironically, to date, this question largely remains unanswered and the number of generations are arbitrarily fixed a priori, with potentially punitive implications. If the a priori fixed generations are insufficient, then the algorithm reports suboptimal solutions. In contrast, if the a priori fixed generations are far too many, it implies waste of computational resources. This paper proposes a novel entropy-based dissimilarity measure that helps identify on the fly the number of generations beyond which an algorithm stabilizes, implying that either a good approximation has been obtained or that it cannot be obtained due to the stagnation of the algorithm in the search space. Given that in either case no further improvement in the approximation can be obtained, despite additional computational expense, the proposed dissimilarity measure provides a termination criterion and facilitates a termination detection algorithm. The generality, on-the-fly implementation, low-computational complexity, and the demonstrated efficacy of the proposed termination detection algorithm, on a wide range of multiobjective and many-objective test problems, define the novel contribution of this paper.
Transferable Intellectual and Personal Skills

Although many employers recruit graduates, often on an any discipline basis, there is an apparent mismatch between employer needs and educational response. Possession of a degree indicates ability to think at a certain level, but is insufficient. Selection criteria, advertisements and training courses run to make graduates fully effective show that employers need skills in communication, co‐operation and teamwork, and positive personal qualities such as the will to set and meet objectives and to be innovative also. American experience indicates that although there is no complete and generally accepted classification of generic intellectual and personal skills, at least some are identifiable and are developed in the process of higher education. The College Outcomes Measures Project identified three ‘process areas’ (communicating, solving problems and clarifying values). The American Programme Evaluation Project identified communication, quantification, analytic and synthesising skills and values clarificat.
Neurolinguistic evidence for rule-based nominal suffixation

This article presents a new set of experimental data from brain-damaged aphasic patients as well as from normals on the processing of two nominal suffixes in Japanese, i.e. -sa and -mi. Their difference with respect to productivity, as confirmed by the experiment on normal adults, provides evidence for the existence of a productive rule-like process in derivational morphology and supports the validity of the dual-mechanism model by integrating derivational morphology in its scope. The experiment on aphasic patients revealed a dissociation, which demonstrates that the two suffixation processes involve two different neurological mechanisms, and provides crucial evidence for the claim that the difference in the productivity of these two suffixes is of a qualitative nature and not a matter of degree.
Production of Recalcitrant Organic Matter under the Influence of Elevated Carbon Dioxide and Temperature

The effects of elevated CO2 and temperature on the quantity and quality of dissolved organic carbon (DOC) of wetland sediments were investigated by measuring organic matter decomposition rates and phenolic compounds as target recalcitrant organic matter. Mean rates of anaerobic microbial metabolism were consistently higher both in vegetated sediments and in elevated CO2 and temperature, although the differences were not statistically significant (P < 0.05). Concentrations of phenolic compounds in sediments with vegetation are significantly different (P < 0.05) from those in sediments without vegetation. Regarding the biodegradability of the phenolic compounds, vegetated sediments showed higher concentrations of 2‐chlorophenol and 2,4‐dimethylphenol under elevated CO2 and temperature conditions, which means that more refractory material can be produced through enhanced organic matter degradation by elevated CO2 and temperature. The produced phenolic compounds can be transported to the freshwater ecosystem and influence the recalcitrance of DOC.
Strategic and Operational Management of Supplier Involvement in New Product Development: A Contingency Perspective

This paper examines how firms succeed to leverage supplier involvement in product development. The paper extends earlier work on managing supplier involvement by providing an integrated analysis of results, processes, and conditions at the level of both the individual development projects and the overall firm. Following a multiple-case study approach with theoretical sampling, the study is carried out by examining eight projects in which four manufacturers from different industries involve multiple suppliers. The findings suggest that successful supplier involvement is dependent on the coordinated design, execution, and evaluation of strategic long-term processes and operational short-term management processes and the presence of enabling factors such as a cross-functional oriented organization. The required intensity of these processes and enablers depends on contingencies such as firm size and environmental uncertainty. In contrast with previous research, we find no indications that managing supplier involvement requires a different approach in highly innovative projects compared to less-innovative projects.
The Anticancer Effect of Fucoidan in PC-3 Prostate Cancer Cells

Fucoidan, a sulfated polysaccharide, has a variety of biological activities, such as anti-cancer, anti-angiogenic and anti-inflammatory. However, the mechanisms of action of fucoidan as an anti-cancer agent have not been fully elucidated. The present study examined the anti-cancer effect of fucoidan obtained from Undaria pinnatifida in PC-3 cells, human prostate cancer cells. Fucoidan induced the apoptosis of PC-3 cells by activating both intrinsic and extrinsic pathways. The induction of apoptosis was accompanied by the activation of extracellular signal-regulated kinase mitogen-activated protein kinase (ERK1/2 MAPK) and the inactivation of p38 MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt. In addition, fucoidan also induced the up-regulation of p21Cip1/Waf and down-regulation of E2F-1 cell-cycle-related proteins. Furthermore, in the Wnt/β-catenin pathway, fucoidan activated GSK-3β that resulted in the decrease of β-catenin level, followed by the decrease of c-myc and cyclin D1 expressions, target genes of β-catenin in PC-3 cells. These results suggested that fucoidan treatment could induce intrinsic and extrinsic apoptosis pathways via the activation of ERK1/2 MAPK, the inactivation of p38 MAPK and PI3K/Akt signaling pathway, and the down-regulation of Wnt/β-catenin signaling pathway in PC-3 prostate cancer cells. These data support that fucoidan might have potential for the treatment of prostate cancer.