Miracle-dz/UniFAR-FTUs huggingface dataset:
Rapid release of antipsychotic drugs from dopamine D2 receptors: an explanation for low receptor occupancy and early clinical relapse upon withdrawal of clozapine or quetiapine.

OBJECTIVE In an attempt to understand the basis of early relapse after antipsychotic withdrawal, the objective of this study was to determine whether the low occupancy of dopamine D2 receptors by clozapine and by quetiapine, as seen by brain imaging, could arise from a rapid release of some of the D2-bound clozapine or quetiapine by the brain imaging compounds and by the action of a physiological concentration of dopamine. METHOD Human cloned D2 receptors were first pre-equilibrated with the [3H]antipsychotic drug, after which raclopride, iodobenzamide, or dopamine (at the physiological concentration in the synapse) was added, and the time course of release of the [3H]antipsychotic from the D2 receptor was measured. RESULTS Within 5 minutes, low concentrations of raclopride and iodobenzamide displaced appreciable amounts of [3H]clozapine and [3H]quetiapine from the D2 receptors but, during the course of 1 hour, did not displace any of the other antipsychotic [[3H]ligands. [3H]Clozapine and [3H]quetiapine, moreover, were displaced by dopamine (100 nM) at least 100 times faster than the other antipsychotic [3H]ligands. CONCLUSIONS Clozapine and quetiapine are loosely bound to the D2 receptor, and the injected radioactive ligand at its peak concentration may displace some of the D2-bound antipsychotic drug, resulting in apparently low D2 occupancies. Therefore, under clinical brain imaging conditions with [11C]raclopride, D2 occupancies by clozapine and by quetiapine may be higher than currently estimated. These considerations may result in high levels of the D2 receptors being occupied by therapeutic doses of clozapine or quetiapine. The rapid release of clozapine and quetiapine from D2 receptors by endogenous dopamine may contribute to low D2 receptor occupancy and to early clinical relapse upon withdrawal of these medications.
Serotonin Receptor Activation of Phosphoinositide Turnover in Uterine, Fundal, Vascular, and Tracheal Smooth Muscle

Hydrolysis of phosphatidylinositul is becoming recognized as the second messenger system for a number of hormones and neurotransmitters, including serotonin. The present study was designed to explore the effects of serotonin to enhance phosphoinositide turnover in several smooth muscle preparations, in an effort (a) to determine which smooth muscle preparation might provide a useful system for further study of phosphoinositide turnover and (b) to examine the role of 5-HT2 receptors in such responses. Basal-[3H] IP(inositol monophosphate ([3H]IP) formation was 10-fold higher in the uterus than in the rat jugular vein, aorta, stomach fundus, or guinea pig trachea. Serotonin produced significant elevations in [3H]IP in the rat aorta, uterus, and jugular vein. Maximal elevation in pH IP was greatest in the jugular vein (eightfold increase) with an ED50 for serotonin of 0.4 (xM. Serotonin (10-7-10−4 M),although a potent contractile agonist in both the guinea pig trachea and rat stomach fundus, did not increase levels in these tissues. The selective 5-HT2 receptor blocker LY53857 (105 M) antagonized the increase in [3H]IP produced by serotonin in the jugular vein, aorta, and uterus. Pargyline (10−6M) added to the trachea and fundus did not unmask an effect of serotonin or enhance the response to serotonin in the rat aorta. Thus, the jugular vein was the tissue most sensitive to activation of pH]IP by serotonin. Increases in PH]IP produced by serotonin may be linked to activation of 5-HT2 receptors in the jugular vein, aorta, and uterus since the selective 5-HT2 antagonist LY53857 could block this biochemical effect. Furthermore, since the guinea pig trachea, like the rat jugular vein, aorta, and uterus, possesses 5-HT: receptors that mediate the contractile response to serotonin and since serotonin did not significantly elevate [3H]IP in the guinea pig trachea, we conclude that activation of 5-HT, receptors may not always result in a measurable increase in [3H]IP.
Pharmacoinformatic and molecular docking studies reveal potential novel antidepressants against neurodegenerative disorders by targeting HSPB8

Charcot–Marie–Tooth (CMT) disease is an inherited peripheral neuromuscular disorder characterized by length-dependent and progressive degeneration of peripheral nerves, leading to muscular weakness. Research has shown that mutated HSPB8 may be responsible for depression, neurodegenerative disorders, and improper functioning of peripheral nerves, resulting in neuromuscular disorders like CMT. In the current work, a hybrid approach of virtual screening and molecular docking studies was followed by homology modeling and pharmacophore identification. Detailed screening analyses were carried out by 2-D similarity search against prescribed antidepressant drugs with physicochemical properties. LigandScout was employed to ascertain novel molecules and pharmacophore properties. In this study, we report three novel compounds that showed maximum binding affinity with HSPB8. Docking analysis elucidated that Met37, Ser57, Ser58, Trp60, Thr63, Thr114, Lys115, Asp116, Gly117, Val152, Val154, Leu186, Asp189, Ser190, Gln191, and Glu192 are critical residues for ligand–receptor interactions. Our analyses suggested paroxetine as a potent compound for targeting HSPB8. Selected compounds have more effective energy scores than the selected drug analogs. Additionally, site-directed mutagenesis could be significant for further analysis of the binding pocket. The novel findings based on an in silico approach may be momentous for potent drug design against depression and CMT.
Assessing eLearning Systems in the Kingdom of Saudi Arabia’s Higher Education Sector: An exploratory analysis

A new challenge for universities in the Muslim world, including the Kingdom of Saudi Arabia (KSA), is the need to develop suitable eLearning systems to facilitate distance learning and culturally acceptable mixed gender collaboration. This paper is a work-in-progress report on research being conducted on the assessment of eLearning systems in KSA. Our conceptual framework is the IS Success/Impact Measurement framework pioneered by DeLone & McLean (1992) and extended by Gable, Sedera & Chan [1]. We propose a range of indicators/items to measure the four dimensions of success and impact of an eLearning system as modelled by this framework.
A Human Minor Histocompatibility Antigen Specific for B Cell Acute Lymphoblastic Leukemia

Human minor histocompatibility antigens (mHags) play an important role in the induction of cytotoxic T lymphocyte (CTL) reactivity against leukemia after human histocompatibility leukocyte antigen (HLA)-identical allogeneic bone marrow transplantation (BMT). As most mHags are not leukemia specific but are also expressed by normal tissues, antileukemia reactivity is often associated with life-threatening graft-versus-host disease (GVHD). Here, we describe a novel mHag, HB-1, that elicits donor-derived CTL reactivity in a B cell acute lymphoblastic leukemia (B-ALL) patient treated by HLA-matched BMT. We identified the gene encoding the antigenic peptide recognized by HB-1–specific CTLs. Interestingly, expression of the HB-1 gene was only observed in B-ALL cells and Epstein-Barr virus–transformed B cells. The HB-1 gene–encoded peptide EEKRGSLHVW is recognized by the CTL in association with HLA-B44. Further analysis reveals that a polymorphism in the HB-1 gene generates a single amino acid exchange from His to Tyr at position 8 within this peptide. This amino acid substitution is critical for recognition by HB-1–specific CTLs. The restricted expression of the polymorphic HB-1 Ag by B-ALL cells and the ability to generate HB-1–specific CTLs in vitro using peptide-loaded dendritic cells offer novel opportunities to specifically target the immune system against B-ALL without the risk of evoking GVHD.
Isolation and characterization of the Escherichia coli msbB gene, a multicopy suppressor of null mutations in the high-temperature requirement gene htrB

Previous work established that the htrB gene of Escherichia coli is required for growth in rich media at temperatures above 32.5 degrees C but not at lower temperatures. In an effort to determine the functional role of the htrB gene product, we have isolated a multicopy suppressor of htrB, called msbB. The msbB gene has been mapped to 40.5 min on the E. coli genetic map, in a 12- to 15-kb gap of the genomic library made by Kohara et al. (Y. Kohara, K. Akiyama, and K. Isono, Cell 50:495-508, 1987). Mapping data show that the order of genes in the region is eda-edd-zwf-pykA-msbB. The msbB gene codes for a protein of 37,410 Da whose amino acid sequence is similar to that of HtrB and, like HtrB, the protein is very basic in nature. The similarity of the HtrB and MsbB proteins could indicate that they play functionally similar roles. Mutational analysis of msbB shows that the gene is not essential for E. coli growth; however, the htrB msbB double mutant exhibits a unique morphological phenotype at 30 degrees C not seen with either of the single mutants. Analysis of both msbB and htrB mutants shows that these bacteria are resistant to four times more deoxycholate than wild-type bacteria but not to other hydrophobic substances. The addition of quaternary ammonium compounds rescues the temperature-sensitive phenotype of htrB bacteria, and this rescue is abolished by the simultaneous addition of Mg2+ or Ca2+. These results suggest that MsbB and HtrB play an important role in outer membrane structure and/or function.
A new sense of protection: role of the Ca2+-sensing receptor in ischemic preconditioning.

the phenomenon of ischemic preconditioning (IPC), a condition in which brief periods of ischemia increase the tolerance of the heart to subsequent ischemic injury, is of immense clinical interest. Many signaling pathways are implicated in the induction of IPC; however, the initiation of the response involves activation of G protein-coupled receptors (GPCRs) and their downstream effectors (e.g., a variety of prosurvival kinase cascades) that ultimately converge to inhibit the opening of the mitochondrial permeability transition pore and limit subsequent proapoptotic activity (2, 4).
LncRNA HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2

Long non-coding RNA HOTAIR predicts negative tumor prognosis and exhibits oncogenic activity. Herein, we demonstrate HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2. Mechanistically, HOTAIR reduces the recuritment of the CREB, P300, RNA polII onto the SETD2 promoter region that inhibits SETD2 expression and its phosphorylation. Thereby, the SETD2 binding capacity to substrate histone H3 is weakened, triggering a reduction of trimethylation on histone H3 thirty-sixth lysine, and thereby the H3K36me3–hMSH2-hMSH6-SKP2 complex is also decreased. Strikingly, the complex occupancy on chromosome is depressed, preventing from mismatch DNA repair. While reducing the degradation capacity of Skp2 for aging histone H3 bound to damaged DNA, the aging histone repair is impaired. Furthermore, that the damaged DNA escaped to repair can causes microsatellite instability(MSI) and abnormal expression of cell cycle related genes that may trigger the hepatocarcinogenesis. This study provides evidence for HOTAIR to promote tumorigenesis via downregulating SETD2 in liver cancer stem cells.
Competing generic concepts for Blanding's, Pacific and European pond turtles (Emydoidea, Actinemys and Emys)—Which is best?

We review competing taxonomic classifications and hypotheses for the phylogeny of emydine turtles. The formerly recognized genus Clemmys sensu lato clearly is paraphyletic. Two of its former species, now Glyptemys insculpta and G. muhlenbergii, constitute a well-supported basal clade within the Emydinae. However, the phylogenetic position of the other two species traditionally placed in Clemmys remains controversial. Mitochondrial data suggest a clade embracing Actinemys (formerly Clemmys) marmorata, Emydoidea and Emys and as its sister either another clade (Clemmys guttata + Terrapene) or Terrapene alone. In contrast, nuclear genomic data yield conflicting results, depending on which genes are used. Either Clemmys guttata is revealed as sister to ((Emydoidea + Emys) + Actinemys) + Terrapene or Clemmys guttata is sister to Actinemys marmorata and these two species together are the sister group of (Emydoidea + Emys); Terrapene appears then as sister to (Actinemys marmorata + Clemmys guttata) + (Emydoidea + Emys). The contradictory branching patterns depending from the selected loci are suggestive of lineage sorting problems. Ignoring the unclear phylogenetic position of Actinemys marmorata, one recently proposed classification scheme placed Actinemys marmorata, Emydoidea blandingii, Emys orbicularis, and Emys trinacris in one genus (Emys), while another classification scheme treats Actinemys, Emydoidea, and Emys as distinct genera. The inclusion of Actinemys in the same taxon as Emydoidea + Emys is unacceptable under a phylogenetic classification framework because there is evidence for the non-monophyly of this clade. Moreover, Actinemys, Emydoidea, and Emys are morphologically highly distinct. Their morphological divergence exceeds by far the differences that typically occur among species of the same genus, so that a continued usage of the distinct genera Actinemys, Emydoidea and Emys is recommended.
Long-Term Oral Administration of Dipyridamole Improves Both Cardiac and Physical Status in Patients with Mild to Moderate Chronic Heart Failure: A Prospective Open-Randomized Study

Adenosine is known as an endogenous cardioprotectant. We previously reported that plasma adenosine levels increase in patients with chronic heart failure (CHF), and that a treatment that further elevates plasma adenosine levels may improve the pathophysiology of CHF. Therefore, we performed a prospective, open-randomized clinical trial to determine whether or not exposure to dipyridamole for 1 year improves CHF pathophysiology compared with conventional treatments. The study enrolled 28 patients (mean±SEM: 66±4 years of age) attending specialized CHF outpatient clinics with New York Heart Association (NYHA) class II or III, no major complications, and stable CHF status during the most recent 6 months under fixed medications. They were randomized into three groups with or without dipyridamole (Control: n=9; 75 mg/day: n=9; 300 mg/day: n=10) in addition to their original medications and were followed up for 1 year. The other drugs were not altered. Among the enrolled patients, 100%, 4%, 100%, and 79% received angiotensin-converting enzyme inhibitors, aldosterone analogue, loop diuretics, and β-adrenoceptor blocker, respectively. Fifteen patients suffered from dilated cardiomyopathy, and 7/3/3 patients suffered from ischemic/valvular/hypertensive heart diseases, respectively. Mean blood pressure was comparable among the groups. While the baseline conditions were comparable, we found that echocardiographic ejection fraction (p<0.01 vs. baseline, p<0.01 vs. Control), left ventricular systolic diameter (p<0.05, p<0.05), Specific Activity Scale (SAS) score (p<0.05, p<0.01), maximal oxygen consumption (p<0.05, p<0.05) and plasma B-type natriuretic peptide level (p<0.01, p<0.01) were significantly improved in patients with dipyridamole after 1 year, generally in a dose-dependent manner. Therefore, we suggest that an additional administration of dipyridamole further improves CHF pathophysiology.
Chemical Evolution of Galaxies and Intracluster Medium

In this series of lectures I discuss the basic principles and the modelling of the chemical evolution of galaxies. In particular, I present models for the chemical evolution of the Milky Way galaxy and compare them with the available observational data. From this comparison one can infer important constraints on the mechanism of formation of the Milky Way as well as on stellar nucleosynthesis and supernova progenitors. Models for the chemical evolution of elliptical galaxies are also shown in the framework of the two competing scenarios for galaxy formation: monolithic and hierachical. The evolution of dwarf starbursting galaxies is also presented and the connection of these objects with Damped Lyman-alpha systems is briefly discussed. The roles of supernovae of different type (I, II) is discussed in the general framework of galactic evolution and in connection with the interpretation of high redshift objects. Finally, the chemical enrichment of the intracluster medium as due mainly to ellipticals and S0 galaxies is discussed.
Impact of the Infection Period Distribution on the Epidemic Spread in a Metapopulation Model

Epidemic models usually rely on the assumption of exponentially distributed sojourn times in infectious states. This is sometimes an acceptable approximation, but it is generally not realistic and it may influence the epidemic dynamics as it has already been shown in one population. Here, we explore the consequences of choosing constant or gamma-distributed infectious periods in a metapopulation context. For two coupled populations, we show that the probability of generating no secondary infections is the largest for most parameter values if the infectious period follows an exponential distribution, and we identify special cases where, inversely, the infection is more prone to extinction in early phases for constant infection durations. The impact of the infection duration distribution on the epidemic dynamics of many connected populations is studied by simulation and sensitivity analysis, taking into account the potential interactions with other factors. The analysis based on the average nonextinct epidemic trajectories shows that their sensitivity to the assumption on the infectious period distribution mostly depends on , the mean infection duration and the network structure. This study shows that the effect of assuming exponential distribution for infection periods instead of more realistic distributions varies with respect to the output of interest and to other factors. Ultimately it highlights the risk of misleading recommendations based on modelling results when models including exponential infection durations are used for practical purposes.
Congestion-Aware Network-Coding-Based Opportunistic Routing in Wireless Ad Hoc Networks

In this paper, we propose a congestion-aware network-coding-based opportunistic routing mechanism called CONCOR for wireless ad hoc networks. An existing mechanism called MORE shows good throughput in the single flow case; however, it suffers significant performance degradation in scenarios with multiple traffic flows due to the redundant transmission problem and the unbalanced load problem. To tackle these two problems, our proposed CONCOR contains two key components, namely, null space feedback and rank differential, which allows feedback of the received random network coding information with minimal overhead among neighboring nodes and enables a backpressure policy to balance the load along the path. The simulation results show that CONCOR outperforms MORE in all cases, even in the single flow scenario. Specifically, compared with MORE, CONCOR has better throughput due to fewer redundant transmissions and more equitable treatment of multiple competing flows.
Evolution of high duty cycle echolocation in bats

Summary Duty cycle describes the relative ‘on time’ of a periodic signal. In bats, we argue that high duty cycle (HDC) echolocation was selected for and evolved from low duty cycle (LDC) echolocation because increasing call duty cycle enhanced the ability of echolocating bats to detect, lock onto and track fluttering insects. Most echolocators (most bats and all birds and odontocete cetaceans) use LDC echolocation, separating pulse and echo in time to avoid forward masking. They emit short duration, broadband, downward frequency modulated (FM) signals separated by relatively long periods of silence. In contrast, bats using HDC echolocation emit long duration, narrowband calls dominated by a single constant frequency (CF) separated by relatively short periods of silence. HDC bats separate pulse and echo in frequency by exploiting information contained in Doppler-shifted echoes arising from their movements relative to background objects and their prey. HDC echolocators are particularly sensitive to amplitude and frequency glints generated by the wings of fluttering insects. We hypothesize that narrowband/CF calls produced at high duty cycle, and combined with neurobiological specializations for processing Doppler-shifted echoes, were essential to the evolution of HDC echolocation because they allowed bats to detect, lock onto and track fluttering targets. This advantage was especially important in habitats with dense vegetation that produce overlapping, time-smeared echoes (i.e. background acoustic clutter). We make four specific, testable predictions arising from this hypothesis.
Evaluating delight in the user experience of smartphones: case Nokia

This case study describes a method and a practice developed at Nokia where we assessed the degree of delight in the user experience of smartphones, and advocated ways to design for more delightful experiences. The described method combines competitive analysis, qualitative assessment and numeric scoring on design. The purpose of the method was to advocate designs that users would potentially experience as more delightful than competitors. Through examples, we describe how we constructed the heuristic and the measure of delight in UX and discuss the contributions, limitations and evolution of the evaluation practice within the company.
Connectionist Semantic Systematicity in Language Production

A novel connectionist model of sentence production is presented, which employs rich situation model representations originally proposed for modeling systematicity in comprehension (Frank, Haselager, & van Rooij, 2009). The high overall performance of our model demonstrates that such representations are not only suitable for comprehension, but also for modeling language production. Further, the model is able to produce novel encodings (active vs. passive) for a particular semantics, as well as generate such encodings for previously unseen situations, thus demonstrating both syntactic and semantic systematicity. Our results provide yet further evidence that such connectionist approaches can achieve systematicity, in production as well as comprehension.
A division in PIN-mediated patterning during lateral organ initiation in grasses : Computational model description

The objective of the computational model is to verify whether the conceptual model of auxin transport and polarization of PIN1a, PIN1b and SoPIN1 proteins postulated in the paper can plausibly capture the experimentally observed spatio-temporal pattern of convergence point emergence, vascular strand initiation, and regions of expression and polarities of the three PINs in Brachypodium. The computational model was implemented in C++ using the VVE system (an extension of the Vertex-Vertex (VV) system [1]), which provides a data-structure and libraries for representing cellular tissues.
Health Impact Assessment: Development of a Full-Service Grocery Store Within a Food Desert

2 The mission of the Center for Health Policy is to conduct research on critical health-related issues and translate data into evidence-based policy recommendations to improve community health. The CHP faculty and staff collaborate with public and private partners to conduct quality data driven program evaluation and applied research analysis on relevant public health issues. The Center serves as a bridge between academic health researchers and federal, state and local government as well as healthcare and community organizations. AbstrAct Using the methods of a Health Impact Assessment , this report is intended to determine potential intended and unintended health-related consequences which may result from the development of a full-service grocery store within a federally designated food desert in Indianapolis, Indiana.