Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of N-Substituted Analogs of Benztropine: Diminished Cocaine-Like Effects in Dopamine Transporter Ligands

Previous studies demonstrated that analogs of benztropine (BZT) possess high affinity for the dopamine transporter, inhibit dopamine uptake, but generally have behavioral effects different from those of cocaine. One hypothesis is that muscarinic-M1 receptor actions interfere with cocaine-like effects. Several tropane-nitrogen substitutions of 4′,4′′-diF-BZT have reduced M1 affinity compared with the CH3-analog (AHN 1-055; 3α-[bis-(4-fluorophenyl)methoxy]tropane). All of the compounds displaced [3H]WIN 35,428 (2β-carbomethoxy-3β-(4-fluorophenyl)tropane) binding with affinities ranging from 11 to 108 nM. Affinities at norepinephrine ([3H]nisoxetine) and serotonin ([3H]citalopram) transporters ranged from 457 to 4810 and 376 to 3260 nM, respectively, and at muscarinic M1 receptors ([3H]pirenzepine) from 11.6 (AHN 1-055) to higher values, reaching 1030 nM for the other BZT-analogs. Cocaine and AHN 1-055 produced dose-related increases in locomotor activity in mice, with AHN 1-055 less effective than cocaine. The other compounds were ineffective in stimulating activity. In rats discriminating cocaine (29 μmol/kg i.p.) from saline, WIN 35,428 fully substituted for cocaine, whereas AHN 1-055 produced a maximal substitution of 79%. None of the other analogs fully substituted for cocaine. WIN 35,428 produced dose-related leftward shifts in the cocaine dose-effect curve, whereas selected BZT analogs produced minimal changes in the effects of cocaine. The results suggest that reducing M1 affinity of 4′,4′′-diF-BZT with N-substitutions reduces effectiveness in potentiating the effects of cocaine. Furthermore, although the BZT-analogs bind with high affinity at the dopamine transporter, their behavioral effects differ from those of cocaine. These compounds have reduced efficacy compared with cocaine, a long duration of action, and may serve as leads for the development of medications to treat cocaine abuse.
Differential Acquisition, Extinction, and Reinstatement of Conditioned Suppression in Mice

In animals, the reappearance of conditioned fear responses after extinction has been primarily investigated using single-cue conditioning paradigms. However, a differential paradigm can overcome several of the disadvantages associated with a single-cue procedure. In the present study, the reinstatement phenomenon was assessed in mice using a differential conditioned suppression paradigm. In a first phase, one conditioned stimulus (CS +) was consistently paired with an unconditioned stimulus (US; footshock) while another CS (CS–) was not, resulting in selective suppression of previously trained instrumental behaviour during the CS +. After the extinction phase, half of the animals (reinstatement group) were presented with unsignalled USs, while the other half were not (control group). A differential return of conditioned responding was observed in the reinstatement group, but not in the control group. The implications of these findings for future conditioning research are discussed.
B-cell receptor activation inhibits AID expression through calmodulin inhibition of E-proteins

Upon encountering antigens, B-lymphocytes can adapt to produce a highly specific and potent antibody response. Somatic hypermutation, which introduces point mutations in the variable regions of antibody genes, can increase the affinity for antigen, and antibody effector functions can be altered by class switch recombination (CSR), which changes the expressed constant region exons. Activation-induced cytidine deaminase (AID) is the mutagenic antibody diversification enzyme that is essential for both somatic hypermutation and CSR. The mutagenic AID enzyme has to be tightly controlled. Here, we show that engagement of the membrane-bound antibodies of the B-cell receptor (BCR), which signals that good antibody affinity has been reached, inhibits AID gene expression and that calcium (Ca2+) signaling is essential for this inhibition. Moreover, we show that overexpression of the Ca2+ sensor protein calmodulin inhibits AID gene expression, and that the transcription factor E2A is required for regulation of the AID gene by the BCR. E2A mutated in the binding site for calmodulin, and thus showing calmodulin-resistant DNA binding, makes AID expression resistant to the inhibition through BCR activation. Thus, BCR activation inhibits AID gene expression through Ca2+/calmodulin inhibition of E2A.
Good Booms, Bad Booms

Credit booms are not rare, some end in a crisis (bad booms) whereas others do not (good booms). We document that credit booms start with an increase in productivity growth, which subsequently falls faster during bad booms. We develop a model in which a crisis happens when a credit boom transits toward an information regime with careful examination of collateral. As this examination is more valuable when collateral backs projects with low productivity, crises are more likely during booms that display larger productivity declines. We test the main predictions of the model and identify the default probability as the main component of measured productivity that lies behind crises.
The analgesic properties of numorphan (14-hydroxy dihydromorphinone), a new synthetic narcotic.

SINCE the discovery of morphine a ceaseless effort has been made to improve its somnifacient and analgesic effects, and at the same time to decrease the undesirable reactions. In the past fifty years many drugs with morphinelike activity have resulted from these efforts. Some of these drugs resemble morphine and are modifications of the naturally occurring alkaloids; others are produced synthetically. Numorphan (14-hydroxy dihydromorphinone hydrochloride),§ a synthetic derivative of the alkaloid morphine (Fig. 1), differs from Dilaudid by the addition of a hydroxyl group at the fourteenth position — a change that is purported to increase its analgesic properties.1 It .
Thermo‐Oxidative Degradation during Creep Crack Growth of PE‐HD Grades as Assessed by FT‐IR Spectroscopy

Creep crack growth experiments under static loads were done with two polyethylene high density (PE-HD) types stabilised in two different ways. The degree of oxidation at the cracks was estimated by CO-numbers measured with FT-IR spectroscopy. The CO-number is the ratio of the peak of oxidation products at approx. 1720 cm -1 to an inherent PE-HD-peak at 2020 cm -1 and represents a direct measure for oxidative damage. Higher CO-numbers could be measured near the crack surfaces. However, this phenomenon could only be found in the low crack growth rate regime, where sufficient time is available for oxidation processes to take place. Moreover, local ageing decreases very quickly in some distance away from the crack path. A direct influence of different stabiliser systems on the degree of these local ageing processes could not be found.
High‐Performance Organic Field‐Effect Transistors

With the advent of devices based on single crystals, the performance of organic field‐effect transistors has experienced a significant leap, with mobility now in excess of 10 cm2 V−1 s−1. The purpose of this review is to give an overview of the state‐of‐the‐art of these high‐performance organic transistors. The paper focuses on the problem of parameter extraction, limitations of the performance by the interfaces, which include the dielectric–semiconductor interface, and the injection and retrieval of charge carriers at the source and drain electrodes. High‐performance devices also constitute tools of choice for investigating charge transport phenomena in organic materials. It is shown how the combination of field‐effect measurements with other electrical characterizations helps in elucidating this still unresolved issue.
Younger age, female sex, and high number of awakenings and arousals predict fatigue in patients with sleep disorders: a retrospective polysomnographic observational study

Background The Fatigue Severity Scale (FSS) is widely used to assess fatigue, not only in the context of multiple sclerosis-related fatigue, but also in many other medical conditions. Some polysomnographic studies have shown high FSS values in sleep-disordered patients without multiple sclerosis. The Modified Fatigue Impact Scale (MFIS) has increasingly been used in order to assess fatigue, but polysomnographic data investigating sleep-disordered patients are thus far unavailable. Moreover, the pathophysiological link between sleep architecture and fatigue measured with the MFIS and the FSS has not been previously investigated. Methods This was a retrospective observational study (n = 410) with subgroups classified according to sleep diagnosis. The statistical analysis included nonparametric correlation between questionnaire results and polysomnographic data, age and sex, and univariate and multiple logistic regression. Results The multiple logistic regression showed a significant relationship between FSS/MFIS values and younger age and female sex. Moreover, there was a significant relationship between FSS values and number of arousals and between MFIS values and number of awakenings. Conclusion Younger age, female sex, and high number of awakenings and arousals are predictive of fatigue in sleep-disordered patients. Further investigations are needed to find the pathophysiological explanation for these relationships.
Tumor Suppressor MicroRNA-27a in Colorectal Carcinogenesis and Progression by Targeting SGPP1 and Smad2

The aberrant expression of microRNAs (miRNAs) is associated with colorectal carcinogenesis, but the underlying mechanisms are not clear. This study showed that the miRNA-27a (miR-27a) was significantly reduced in colorectal cancer tissues and colorectal cancer cell lines, and that the reduced miR-27a was associated with distant metastasis and colorectal cancer clinical pathological stages–miR-27a was lower at stages III/IV than that at stage II. Bioinformatic and systemic biological analysis predicted several targets of miR-27a, among them SGPP1 and Smad2 were significantly affected. SGPP1 and Smad2 at mRNA and protein levels were negatively correlated with miR-27a in human colorectal cancer tissues and cancer cell lines. Increased miR-27a significantly repressed SGPP1 and Smad2 at transcriptional and translational levels. Functional studies showed that increasing miR-27a inhibited colon cancer cell proliferation, promoted apoptosis and attenuated cell migration, which were also linked to downregulation of p-STAT3 and upregulation of cleaved caspase 3. In vivo, miR-27a inhibited colon cancer cell growth in tumor-bearing mice. Taken together, this study has revealed miR-27a as a tumor suppressor and has identified SGPP1 and Smad2 as novel targets of miR-27a, linking to STAT3 for regulating cancer cell proliferation, apoptosis and migration in colorectal cancer. Therefore, miR-27a could be a useful biomarker for monitoring colorectal cancer development and progression, and also could have a therapeutic potential by targeting SGPP1, Smad2 and STAT3 for colorectal cancer therapy.
Coronavirus Replicase-Reporter Fusions Provide Quantitative Analysis of Replication and Replication Complex Formation

ABSTRACT The replication of coronaviruses occurs in association with multiple virus-induced membrane structures that evolve during the course of infection; however, the dynamics of this process remain poorly understood. Previous studies of coronavirus replication complex organization and protein interactions have utilized protein overexpression studies and immunofluorescence of fixed cells. Additionally, live-imaging studies of coronavirus replicase proteins have used fluorescent reporter molecules fused to replicase proteins, but expressed from nonnative locations, mostly late-transcribed subgenomic mRNAs, in the presence or absence of the native protein. Thus, the timing and targeting of native replicase proteins expressed in real time from native locations in the genome remain unknown. In this study, we tested whether reporter molecules could be expressed from the replicase polyprotein of murine hepatitis virus as fusions with nonstructural protein 2 or 3 and whether such reporters could define the targeting and activity of replicase proteins during infection. We demonstrate that the fusion of green fluorescent protein and firefly luciferase with either nonstructural protein 2 or 3 is tolerated and that these reporter-replicase fusions can be used to quantitate replication complex formation and virus replication. The results show that the replicase gene has flexibility to accommodate a foreign gene addition and can be used directly to study replicase complex formation and evolution during infection as well as to provide highly sensitive and specific markers for protein translation and genome replication. IMPORTANCE Coronaviruses are a family of enveloped, positive-sense RNA viruses that are important agents of disease, including severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus. Replication is associated with multiple virus-induced membrane structures that evolve during infection; however, the dynamics of this process remain poorly understood. In this study, we tested whether reporter molecules expressed from native locations within the replicase polyprotein of murine hepatitis virus as fusions with nonstructural proteins could define the expression and targeting of replicase proteins during infection in live cells. We demonstrate that the replicase gene tolerates the introduction of green fluorescent protein or firefly luciferase as fusions with replicase proteins. These viruses allow early quantitation of virus replication as well as real-time measurement of replication complexes.
Offline grammar-based recognition of handwritten sentences

This paper proposes a sequential coupling of a hidden Markov model (HMM) recognizer for offline handwritten English sentences with a probabilistic bottom-up chart parser using stochastic context-free grammars (SCFG) extracted from a text corpus. Based on extensive experiments, we conclude that syntax analysis helps to improve recognition rates significantly.
Oscillatory Brain Responses Evoked by Video Game Events: The Case of Super Monkey Ball 2

Electroencephalography (EEG) was recorded while the subjects played a video game where the player had to steer a monkey into a goal while collecting bananas for extra points and had to avoid falling off the edge of the game board. Each of these three studied events evoked differential EEG oscillatory changes. Picking up bananas evoked decreased theta activation on central electrodes, decreased high alpha activation on frontal electrodes, and increased beta activation on frontal electrodes. Falling off the game board evoked decreased central theta activation and increased fronto-central beta activation. Reaching the goal evoked increased theta activation on parietal electrodes, increased low alpha activation on frontal electrodes, increased high alpha activation on frontal, central, and parietal electrodes, and increased beta activation on frontal and central electrodes. It is suggested that the EEG oscillations evoked by picking up bananas reflect increased cortical activation and arousal; the oscillations evoked by falling off the edge of the game board reflect motor functions; and the oscillations evoked by reaching the goal reflect a relaxed state. Thus, EEG may turn out to be a valuable tool when examining psychological responses to video game events.
Lack of Functional P-Selectin Ligand Exacerbates Salmonella Serovar Typhimurium Infection1

The selectin family of adhesion molecules mediates the recruitment of immune cells to the site of inflammation, which is critical for host survival of infection. To characterize the role of selectins in host defense against Salmonella Typhimurium infection, wild-type (WT) mice and mice lacking P-selectin glycoprotein ligand-1 (PSGL-1), P-, E-, or L-selectin, or the glycosyltransferase C2GlcNAcT-I (core 2) were infected using a Salmonella acute gastroenteritis model. Mice were monitored for survival and assessed for intestinal inflammation at 1 and 4 days postinfection. Infected mice lacking core 2, PSGL-1, or P-selectin showed a more pronounced morbidity and a significantly higher mortality rate associated with higher bacterial load and proinflammatory cytokine production, including that of TNF-α, MCP-1, and IL-6, from the colons at 4 days postinfection as compared with WT control. Surprisingly, at 1 day postinfection, more severe inflammation and higher neutrophil infiltration were observed in the ceca of mice lacking core 2, PSGL-1, or P-selectin compared with WT control. Enhanced levels of α4β7+ and MAdCAM-1+ cells were observed in the ceca of infected mice lacking core 2, PSGL-1, or P-selectin. Neutrophil recruitment, cecal inflammation, and mortality rates were dramatically reduced in infected P-selectin knockout mice receiving blocking mAb to α4β7 integrin, indicating that this alternative adhesion molecule may attempt to compensate for the loss of selectins in neutrophil recruitment. These results demonstrate a definitive phenotypic abnormality in mice lacking core 2, PSGL-1, or P-selectin, suggesting that the interaction of functional PSGL-1 with P-selectin is an important process in host defense against Salmonella infection.
Conclusive Evidence That the Major T-cell Antigens of theMycobacterium tuberculosis Complex ESAT-6 and CFP-10 Form a Tight, 1:1 Complex and Characterization of the Structural Properties of ESAT-6, CFP-10, and the ESAT-6·CFP-10 Complex

The proteins ESAT-6 and CFP-10 have been shown to be secreted by Mycobacterium tuberculosis andMycobacterium bovis cells, to be potent T-cell antigens, and to have a clear but as yet undefined role in tuberculosis pathogenesis. We have successfully overexpressed both ESAT-6 and CFP-10 in Escherichia coli and developed efficient purification schemes. Under in vivo-like conditions, a combination of fluorescence, circular dichroism, and nuclear magnetic resonance spectroscopy have shown that ESAT-6 contains up to 75% helical secondary structure, but little if any stable tertiary structure, and exists in a molten globule-like state. In contrast, CFP-10 was found to form an unstructured, random coil polypeptide. An exciting discovery was that ESAT-6 and CFP-10 form a tight, 1:1 complex, in which both proteins adopt a fully folded structure, with about two-thirds of the backbone in a regular helical conformation. This clearly suggests that ESAT-6 and CFP-10 are active as the complex and raises the interesting question of whether other ESAT-6/CFP-10 family proteins (22 paired genes in M. tuberculosis) also form tight, 1:1 complexes, and if so, is this limited to their genome partner, or is there scope for wider interactions within the protein family, which could provide greater functional flexibility?
A Significance Test-Based Feature Selection Method for the Detection of Prostate Cancer from Proteomic Patterns

ii I hereby declare that I am the sole author of this thesis. This is a true copy of the thesis, including any required final revisions, as accepted by my examiners. I understand that my thesis may be made electronically available to the public. Abstract The work reported in the thesis consists of two parts. One part is concerned with the development of a feature selection method based on statistical significance test, which can be generally used in any supervised pattern classification. The other part applies this proposed feature selection method to conduct proteomic pattern analysis for prostate cancer detection. For a given classification problem, we need to determine a set of relevant features to generate a classifier. In real-world problems, many features in initial feature set are usually irrelevant to the classification task and redundant with each other, which will increase the computational complexity and reduce the recognition rate. The task of feature selection is to choose a small feature subset in order to achieve better classification performance. As such, a novel feature selection method based on statistical significance test is proposed. In the proposed method, the statistical significant difference between (or among) classes is utilized to measure the pattern recognition ability of individual features. The feature significance level during a feature selection procedure is used as a selection criterion, which is determined by the product of the significant difference level and the independent coefficient of the candidate feature. Maximum significant difference and independence (MSDI) algorithm and monotonically increasing curve (MIC) strategy are proposed to sequentially rank the feature significance and to determine minimum number of features to achieve maximum recognition rate. The significance test-based feature selection (STFS) method is computationally effective due to its simple calculation of statistics. In addition, the feature subset selected by STFS has the potential to achieve a better recognition rate than those selected by other heuristic methods (such as the mutual information feature selection method) since the selection criterion (feature significance) is precisely estimated based on the optimal statistical models in accordance with the properties of the data. The application of STFS to benchmark datasets that have a large number of features consistently produces excellent performance. iv The tests for prostate cancer detection currently used in clinics have low sensitivity and specificity. Mass spectrometry-based proteomics provides a promising approach for accuracy detection of prostate cancer. But the properties of the mass spectral data, …
Quantitative Analysis of Gene Expressions Related to Inflammation in Canine Spastic Artery After Subarachnoid Hemorrhage

Background and Purpose— The possible role of inflammatory reaction of the cerebral artery in the pathogenesis of cerebral vasospasm has been noted in recent studies. We quantitatively measured the levels of expression of genes related to inflammation in the spastic artery in a canine double-hemorrhage model. Methods— Twenty dogs were assigned to 4 groups: group D0, control; group D2, dogs killed 2 days after cisternal injection of blood; group D7, dogs given double cisternal injections of blood and killed 7 days after the first injection; and group D14. Angiography was performed twice: on the first day and before the animals were killed. Total RNA was extracted from the basilar artery. The expressions of interleukin (IL)-1&agr;, IL-6, IL-8, IL-10, tumor necrosis factor-&agr;, E-secretin, fibronectin, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule-1, transforming growth factor-&bgr;, basic fibroblast growth factor, and collagen types I, III, and IV were examined with TaqMan real-time quantitative reverse transcription–polymerase chain reaction. Results— Prolonged arterial narrowing peaking on 7 day was observed. There was a significant difference in vessel caliber between D0, D2, D7, and D14 groups (P <0.0001). There were significant differences in mRNA expression in the basilar artery for IL-1&agr;, IL-6, IL-8, ICAM-1, and collagen type I between D0, D2, D7, and D14 groups (P =0.0079, 0.0196, 0.0040, 0.0017, and <0.0001, respectively). The average level of mRNA was highest in D7 for IL-1&agr;, IL-6, IL-8, and ICAM-1 (17-, 16-, 131-, and 1.7-fold compared with those of D0, respectively) and in D14 for collagen type I (10.9-fold). Conclusions— Increased expression of genes related to inflammation in the spastic artery suggests that inflammatory reaction of the cerebral artery is associated with sustained contraction.