gebhart/patrepeval huggingface dataset:
Expression of Listeriolysin O and ActA by Intracellular and ExtracellularListeria monocytogenes (1999)

Listeria monocytogenes requires listeriolysin O (LLO) and ActA, the products of hly and actA, respectively, to establish a productive intracellular infection. LLO is essential for vacuolar lysis and entry into the cytosol, while ActA is required for bacterial spread to adjacent cells. We have used a transcriptional reporter gene system to compare the expression of actA and hly during intracellular growth to that during growth in broth cultures. The hly and actA genes were transcriptionally fused to Escherichia coli lacZ and Bacillus pumilus cat-86 (cat), and the fusions were integrated in single copies into the L. monocytogenes chromosome. A chloramphenicol resistance assay indicated that the hly fusion but not the actA fusion was significantly activated in Luria-Bertani (LB) broth, and this finding correlated with LLO and ActA levels detectable in broth cultures. Quantitation of promoter activity on the basis of beta-galactosidase activity revealed up to 10-fold-higher level of expression of the hly fusion relative to the actA fusion in LB broth. In contrast, both fusions were active in the cytosol of J774 cells, and the activity of the actA fusion was approximately 3-fold higher than that of the hly fusion under these conditions. However, quantitative immunoprecipitation of ActA and LLO from infected J774 cells demonstrated approximately 70-fold more cytosolic ActA than cytosolic LLO. Finally, in comparison to induction in broth cultures, actA was highly induced (226-fold) and hly was moderately induced (20-fold) in J774 cells. Collectively, these results indicate that actA and hly are differentially regulated in response to the growth environment and that both genes are preferentially expressed during intracellular growth. Further, while the lower level of production of ActA than of LLO in broth can be accounted for by transcriptional regulation, the relative abundance of intracellular ActA compared to that of intracellular LLO is a function of additional, possibly host-mediated, factors.
Detection of Protein Biomarkers Using RNA Aptamer Microarrays and Enzymatically Amplified Surface Plasmon Resonance Imaging (2007)

A methodology for the detection of protein biomarkers at picomolar concentrations that utilizes surface plasmon resonance imaging (SPRI) measurements of RNA aptamer microarrays is developed. The adsorption of proteins onto the RNA microarray is detected by the formation of a surface aptamer-protein-antibody complex. The SPRI response signal is then amplified using a localized precipitation reaction catalyzed by the enzyme horseradish peroxidase that is conjugated to the antibody. This enzymatically amplified SPRI methodology is first characterized by the detection of human thrombin at a concentration of 500 fM; the appropriate thrombin aptamer for the sandwich assay is identified from a microarray of three potential thrombin aptamer candidates. The SPRI method is then used to detect the protein vascular endothelial growth factor (VEGF) at a biologically relevant concentration of 1 pM. VEGF is a signaling protein that has been used as a serum biomarker for rheumatoid arthritis, breast cancer, lung cancer, and colorectal cancer and is also associated with age-related macular degeneration.
Statistics and Truth in Phylogenomics (2011)

Phylogenomics refers to the inference of historical relationships among species using genome-scale sequence data and to the use of phylogenetic analysis to infer protein function in multigene families. With rapidly decreasing sequencing costs, phylogenomics is becoming synonymous with evolutionary analysis of genome-scale and taxonomically densely sampled data sets. In phylogenetic inference applications, this translates into very large data sets that yield evolutionary and functional inferences with extremely small variances and high statistical confidence (P value). However, reports of highly significant P values are increasing even for contrasting phylogenetic hypotheses depending on the evolutionary model and inference method used, making it difficult to establish true relationships. We argue that the assessment of the robustness of results to biological factors, that may systematically mislead (bias) the outcomes of statistical estimation, will be a key to avoiding incorrect phylogenomic inferences. In fact, there is a need for increased emphasis on the magnitude of differences (effect sizes) in addition to the P values of the statistical test of the null hypothesis. On the other hand, the amount of sequence data available will likely always remain inadequate for some phylogenomic applications, for example, those involving episodic positive selection at individual codon positions and in specific lineages. Again, a focus on effect size and biological relevance, rather than the P value, may be warranted. Here, we present a theoretical overview and discuss practical aspects of the interplay between effect sizes, bias, and P values as it relates to the statistical inference of evolutionary truth in phylogenomics.
Manipulating the Prion Protein Gene Sequence and Expression Levels with CRISPR/Cas9 (2016)

The mammalian prion protein (PrP, encoded by Prnp) is most infamous for its central role in prion diseases, invariably fatal neurodegenerative diseases affecting humans, food animals, and animals in the wild. However, PrP is also hypothesized to be an important receptor for toxic protein conformers in Alzheimer's disease, and is associated with other clinically relevant processes such as cancer and stroke. Thus, key insights into important clinical areas, as well as into understanding PrP functions in normal physiology, can be obtained from studying transgenic mouse models and cell culture systems. However, the Prnp locus is difficult to manipulate by homologous recombination, making modifications of the endogenous locus rarely attempted. Fortunately in recent years genome engineering technologies, like TALENs or CRISPR/Cas9 (CC9), have brought exceptional new possibilities for manipulating Prnp. Herein, we present our observations made during systematic experiments with the CC9 system targeting the endogenous mouse Prnp locus, to either modify sequences or to boost PrP expression using CC9-based synergistic activation mediators (SAMs). It is our hope that this information will aid and encourage researchers to implement gene-targeting techniques into their research program.
MiR-16 Targets the Serotonin Transporter: A New Facet for Adaptive Responses to Antidepressants (2010)

The serotonin transporter (SERT) ensures the recapture of serotonin and is the pharmacological target of selective serotonin reuptake inhibitor (SSRI) antidepressants. We show that SERT is a target of microRNA-16 (miR-16). miR-16 is expressed at higher levels in noradrenergic than in serotonergic cells; its reduction in noradrenergic neurons causes de novo SERT expression. In mice, chronic treatment with the SSRI fluoxetine (Prozac) increases miR-16 levels in serotonergic raphe nuclei, which reduces SERT expression. Further, raphe exposed to fluoxetine release the neurotrophic factor S100β, which acts on noradrenergic cells of the locus coeruleus. By decreasing miR-16, S100β turns on the expression of serotonergic functions in noradrenergic neurons. Based on pharmacological and behavioral data, we propose that miR-16 contributes to the therapeutic action of SSRI antidepressants in monoaminergic neurons.
Early history of the Decca Navigator system (1985)

The i.f. phase comparison hyperbolic position-fixing technique that became the Decca Navigator was invented in 1937 in the USA. Tests there in 1941, sponsored by the Decca Company, demonstrated an unprecedented position-line accuracy. In the UK the Air Ministry had reservations about the technique but the Admiralty saw it as the possible basis of a navigation system for use on the projected invasion of the French coast. After further development and seagoing trials under the codename QM, the system played a key part (overlooked by historians) in operation Overlord/Neptune of 1944. QM was later employed for hydrographic surveying in the Scheldt estuary. When the system was released for commercial use in 1945 as the Decca Navigator, the design of a lane-identification facility was presenting problems. An intermediate solution (‘Mk. V’) was developed, followed in the 1950s by the ‘Multipulse’ technique used today.
[Allergy to topical antihistamines--discrepancy between the literature and clinical practice]. (1988)

In a prospective study, 100 patients suffering from allergic contact dermatitis were tested for allergy to antihistamines. Diphenhydramine was chosen as test substance because it is the most widely used topical antihistamine in Europe and is, moreover, prescribed for several indications. Not one of the 100 patients proved to react positively on patch testing. The bad reputation among allergists of topically administered antihistamines, which is based on reports in the American literature claiming a high risk of epicutaneous sensitization, thus appears unjustified on the basis of our own data and the lack of European reports of this problem. The adverse findings in the USA may be due to their frequent use of a particularly potent contact sensitizer as emulsifier in topical preparations in general and antihistamines in particular.
Preclinical profile of ITI-214, an inhibitor of phosphodiesterase 1, for enhancement of memory performance in rats (2016)

ITI-214 improved the memory processes of acquisition, consolidation, and retrieval across a broad dose range (0.1-10 mg/kg, po) without disrupting the antipsychotic-like activity of a clinical antipsychotic medication, specifically risperidone. Clinical development of ITI-214 is currently in progress.
Bayesian Calibration of Computer Models (2001)

Summary We consider prediction and uncertainty analysis for systems which are approximated using complex mathematical models. Such models, implemented as computer codes, are often generic in the sense that by a suitable choice of some of the model's input parameters the code can be used to predict the behaviour of the system in a variety of specific applications. However, in any specific application the values of necessary parameters may be unknown. In this case, physical observations of the system in the specific context are used to learn about the unknown parameters. The process of fitting the model to the observed data by adjusting the parameters is known as calibration. Calibration is typically effected by ad hoc fitting, and after calibration the model is used, with the fitted input values, to predict the future behaviour of the system. We present a Bayesian calibration technique which improves on this traditional approach in two respects. First, the predictions allow for all sources of uncertainty, including the remaining uncertainty over the fitted parameters. Second, they attempt to correct for any inadequacy of the model which is revealed by a discrepancy between the observed data and the model predictions from even the best-fitting parameter values. The method is illustrated by using data from a nuclear radiation release at Tomsk, and from a more complex simulated nuclear accident exercise.
Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance (2016)

Therapeutically targeting aberrant intracellular kinase signaling is attractive from a biological perspective but drug development is often hindered by toxicities and inadequate efficacy. Predicting drug behaviors using cellular and animal models is confounded by redundant kinase activities, a lack of unique substrates, and cell-specific signaling networks. Cyclin-dependent kinase (CDK) drugs exemplify this phenomenon because they are reported to target common processes yet have distinct clinical activities. Tumor cell studies of ATP-competitive CDK drugs (dinaciclib, AG-024322, abemaciclib, palbociclib, ribociclib) indicate similar pharmacology while analyses in untransformed cells illuminates significant differences. To resolve this apparent disconnect, drug behaviors are described at the molecular level. Nonkinase binding studies and kinome interaction analysis (recombinant and endogenous kinases) reveal that proteins outside of the CDK family appear to have little role in dinaciclib/palbociclib/ribociclib pharmacology, may contribute for abemaciclib, and confounds AG-024322 analysis. CDK2 and CDK6 cocrystal structures with the drugs identify the molecular interactions responsible for potency and kinase selectivity. Efficient drug binding to the unique hinge architecture of CDKs enables selectivity toward most of the human kinome. Selectivity between CDK family members is achieved through interactions with nonconserved elements of the ATP-binding pocket. Integrating clinical drug exposures into the analysis predicts that both palbociclib and ribociclib are CDK4/6 inhibitors, abemaciclib inhibits CDK4/6/9, and dinaciclib is a broad-spectrum CDK inhibitor (CDK2/3/4/6/9). Understanding the molecular components of potency and selectivity also facilitates rational design of future generations of kinase-directed drugs. Mol Cancer Ther; 15(10); 2273-81. ©2016 AACR.
Physical placement driven by sequential timing analysis (2005)

Traditional timing-driven placement considers only combinational delays and does not take into account the potential of subsequent sequential optimization steps. As a result, the potential of re-balancing path delays through post-placement applications of clock skew scheduling and in-place retiming cannot be fully realized. In this paper we describe a new placement algorithm that is based on a tight integration of sequential timing analysis in the inner loop of an analytic solver. Instead of minimizing the maximum path delay, our approach minimizes the maximum mean delay on any circuit loop, thus enabling the full optimization potential of clock skew scheduling and in-place retiming. We present two versions of the new algorithm: one approximates sequential criticality and weights wires accordingly (Cong and Lim, 2000), the other extends this with the inclusion of explicit wire-length constraints for loops that limit the final clock period. Our algorithms are implemented using a hybrid, GORDlAN-style sequence of analytical placement steps interleaved with cell partitioning (Kleinhans et al., 1988). Our experiments on a set of large industrial designs demonstrate that the presented placement algorithm can minimize the contribution of interconnection delays to the clock period on average by 23.5% compared to a solution based on combinational delays.
The Heterotrophic Connection in a Photoautotrophic Chlorella Vulgaris Dominant in Wastewater Oxidation Ponds (1993)

Chlorella vulgaris strain C1 was grown in laboratory under autotrophic and mixotrophic conditions. Cellular division rates increased in cultures supplied with either acetate or glucose. As a direct result respiratory activity was enhanced in those cells, most pronounced in the presence of acetate. Glucose and acetate had opposed effects on the photosynthetic activity of the cells. Cells grown in the presence of acetate had a 3-fold decrease in pigment contents. Since this was mostly expressed in decreased light utilization efficiency of the cells, we conclude that fewer light harvesting antennae were synthesised. Cells grown with glucose retain high pigment contents and photosynthetic activity of the cells was strongly enhanced. It was observed that even though organic matter may support algal growth in oxidation ponds, at the same time one may expect a much stronger oxygen demand accompanied by a reduced photosynthetic potential. This must be considered a burden on the wastewater treatment operation requiring countermeasures to be taken.
Application of a Novel Ultrasonic Technology to Improve Oil Recovery with an Environmental Viewpoint (2017)

It is proven by recent studies that sonication has a positive influence over the oil flow within the porous media. Accordingly, the researchers in this paper evaluated the influence of sonication over the oil recovery by means of free fall gravity drainage. Furthermore, the influence of sonication on the oil permeability was assessed in three samples that had different bead size in average. By use of the Hagroot backward method and Matlab simulation, the optimal petrophysical situation for sonication was determined. The authors concluded that sonication positively affects the oil recovery for the non-asphaltenic samples, while it has a reverse effect on the asphaltenic samples because of increasing the viscosity in long-term. Furthermore, it was witnessed that gravity drainage was heightened by increase of beads' size in the non-asphaltenic sample. Accordingly, this mechanism can be useful in oil recovery by means of gravity drainage, specifically in fracture reservoirs.
Frataxin Acts as an Iron Chaperone Protein to Modulate Mitochondrial Aconitase Activity (2004)

Numerous degenerative disorders are associated with elevated levels of prooxidants and declines in mitochondrial aconitase activity. Deficiency in the mitochondrial iron-binding protein frataxin results in diminished activity of various mitochondrial iron-sulfur proteins including aconitase. We found that aconitase can undergo reversible citrate-dependent modulation in activity in response to pro-oxidants. Frataxin interacted with aconitase in a citrate-dependent fashion, reduced the level of oxidant-induced inactivation, and converted inactive [3Fe-4S]1+ enzyme to the active [4Fe-4S]2+ form of the protein. Thus, frataxin is an iron chaperone protein that protects the aconitase [4Fe-4S]2+ cluster from disassembly and promotes enzyme reactivation.
Results on generalized Mittag-Leffler function via Laplace transform (2013)

The present paper deals with the results involving Generalized MittagLeffler function by using Laplace Transform.
Cyclophilin A enhances cell proliferation and tumor growth of liver fluke-associated cholangiocarcinoma (2011)

CypA is upregulated in majority of CCA patients' tissues and confers a significant growth advantage in CCA cells. Suppression of CypA expression decreases proliferation of CCA cell lines in vitro and reduces tumor growth in the nude mouse model. Inhibition of CypA activity also reduces CCA cell proliferation. The ERK1/2 pathway may be involved in the CypA-mediated CCA cell proliferation. Thus, CypA may represent an important new therapeutic target for liver fluke-associated CCA.
Effects of systemic administration of oxytocin on contextual fear extinction in a rat model of post-traumatic stress disorder. (2013)

These findings indicate that increasing OXT transmission during fear memory reactivation delays fear extinction, and thus, the recommendation of OXT for PTSD treatment should be considered with caution.
Plasma Ghrelin Levels in Lean and Obese Humans and the Effect of Glucose on Ghrelin Secretion (2002)

Ghrelin, a novel GH-releasing peptide isolated from human and rat stomach, stimulates food intake and GH secretion. We determined plasma ghrelin concentrations in patients with simple obesity, anorexia nervosa, and type 2 diabetes mellitus by RIA. We also studied plasma ghrelin responses to glucose load and meal intake and obtained a 24-h profile of circulating ghrelin in humans. Plasma ghrelin concentrations in patients with simple obesity and anorexia nervosa were lower and higher, respectively, than those of healthy subjects with normal body weight. Among those with type 2 diabetes mellitus, obese patients had lower and lean patients higher fasting plasma ghrelin concentrations than normal-weight patients. Fasting plasma ghrelin concentration was negatively correlated with body mass index in both nondiabetic and diabetic patients. Plasma ghrelin concentrations of normal subjects decreased significantly after oral and iv glucose administration; a similar response was also observed in diabetic patients after a meal tolerance test, reaching a nadir of 69% of the basal level after the meal. Circulating plasma ghrelin showed a diurnal pattern with preprandial increases, postprandial decreases, and a maximum peak at 0200 h. This study demonstrates that nutritional state is a determinant of plasma ghrelin in humans. Ghrelin secretion is up-regulated under conditions of negative energy balance and down-regulated in the setting of positive energy balance. These findings suggest the involvement of ghrelin in the regulation of feeding behavior and energy homeostasis.
Mapping human somatosensory cortex with positron emission tomography (1987)

Positron emission tomography measurements of regional cerebral blood flow were used to detect focal neuronal activation in the first somatosensory cortex (SI) of humans induced by cutaneous vibratory stimulation. Intravenously administered water labeled with oxygen-15 (H2(15)O) was used as a blood flow tracer to obtain five stimulated-state and two resting-state blood flow images in each of eight normal volunteers. Three cutaneous surfaces were tested: lips, fingers, and toes. Intense, highly focal SI responses were seen during all 39 stimulated-state trials. The SI responses from the three stimulation sites were anatomically distinct and formed a medial-to-lateral homonculus in every subject. Response magnitudes (increase in local blood flow) and response locales (expressed as proportionately measured bicommissural stereotaxic coordinates) were highly consistent among subjects and on repeated trials for each subject. These findings suggest that eliciting cerebral blood flow responses by cutaneous vibration provides a safe, rapid, and reproducible tool for locating and assessing the functional status of somatosensory cortex, and offers potential clinical and research utility. This study has established normative values for future applications of this experimental paradigm.
Factor XI in haemostasis and thrombosis: Past, present and future (2007)

T he discipline of haemostasis and thrombosis has set an example, perhapsmore than other disciplines of Medicine, in discoveries based on observations of the so called"experiments of nature".During arelativelyshorttime of 13 years (1947)(1948)(1949)(1950)(1951)(1952)(1953)(1954)(1955)(1956)(1957)(1958)(1959)(1960), most coagulation factorsw ere identifiedinpatients whopresentedwith ableeding tendencyand were worked up by rather simple laboratoryassays. This era of discoveries was followedbythe characterization of the biochemical reactions involved in blood coagulation, delineation of the sequence of reactions in the coagulation pathwaysa nd more recentlyb yu nraveling the molecular genetic aspectsofthe variouscoagulation components. The objective of this reviewistodescribe some of the major developments in understandingthe role of factor (F)XI in haemostasis and thrombosis thath aveo ccurred over more than50years of research,and to highlight recent evidencewhich suggests that FXI deficiencycan have an antithrombotic effect.
A Study of Factors Influencing the Costs of Funding as a Function of Research Area and Financial Institutions (2013)

Purpose: In this paper, we analyzed the factors that affect research grants using linear regression analysis in order to increase the effectiveness of investments in national research projects. Methods: We collected 15,454 pieces of data on research projects that finished between 2008 and 2010. Data preprocessing and visualization were done to derive statistically significant results. We identified factors that affected funding by using linear regression, and estimated increasing or decreasing tendencies based on those factors. Results: We identified the relative importance of the factors in awarding research grants. Strategies were suggested for the reasonable estimation of R&amp;D budgets for investment purposes. Conclusion: This study will assist the decision-making process of governments in estimating funds required for R&amp;D projects.