Miracle-dz/UniFAR-FTUs huggingface dataset:
The Phe-X-Glu DNA Binding Motif of MutS

The crystal structures of MutS protein fromThermus aquaticus and Escherichia coli in a complex with a mismatch-containing DNA duplex reveal that the Glu residue in a conserved Phe-X-Glu motif participates in a hydrogen-bonded contact with either an unpaired thymidine or the thymidine of a G-T base-base mismatch. Here, the role of hydrogen bonding in mismatch recognition by MutS is assessed. The relative affinities of MutS for DNA duplexes containing nonpolar shape mimics of A and T, 4-methylbenzimidazole (Z), and difluorotoluene (F), respectively, that lack hydrogen bonding donors and acceptors, are determined in gel mobility shift assays. The results provide support for an induced fit mode of mismatch binding in which duplexes destabilized by mismatches are preferred substrates for kinking by MutS. Hydrogen bonding between the Oε2 group of Glu and the mismatched base contributes only marginally to mismatch recognition and is significantly less important than the aromatic ring stack with the conserved Phe residue. A MutS protein in which Ala is substituted for Glu38 is shown to be defective for mismatch repairin vivo. DNA binding studies reveal a novel role for the conserved Glu residue in the establishment of mismatch discrimination by MutS.
Towards a definition of glomerulomegaly: clinical–pathological and methodological considerations

Background. Glomerulomegaly, the abnormal enlargement of glomeruli, has been related to an increased risk of glomerulosclerosis, but the degree of enlargement that constitutes glomerulomegaly has not been defined. Methods. The principal stereological methods for estimating glomerular volume are [1] the disector/Cavalieri method that is considered the ‘gold standard’ for measuring individual glomerular volume (IVglom) and [2] the disector/fractionator technique that estimates average glomerular volume (Vglom) together with total glomerular number (Nglom) for the entire kidney. The two methods produce different estimates with Vglom consistently exceeding IVglom. This study compares glomerular volumes obtained by the two methods in autopsy kidneys of 39 African American and 34 US white adult males, and correlates the values with Nglom, body mass index (BMI), hypertension, glomerulosclerosis and race, factors known or thought to influence glomerular volume. Results. For the smallest glomeruli, Vglom was 25% larger than IVglom with the difference increasing to over 50% for kidneys with the largest glomeruli. Both Vglom and IVglom showed significant inverse correlations with Nglom and significant direct correlations with BMI and hypertension. African Americans had larger IVglom and Vglom than whites, but only IVglom was significant. The 90th percentile for IVglom was 6.81 μm3 × 106 and 13.10 μm3 × 106 for Vglom, but larger glomerular size did not separate hypertensive from non-hypertensive subjects nor did it show any significant relationship to glomerulosclerosis. While Vglom overestimated glomerular size compared with IVglom, both measurements demonstrated similar relationships to factors influencing glomerular volume. Conclusions. With neither method could glomerulomegaly, the abnormal enlargement of glomerular size predisposing to glomerulosclerosis, be determined.
Parallel Circuits from Cones to the On‐Beta Ganglion Cell

Neural integration depends critically upon circuit architecture; yet the architecture has never been established quantitatively (numbers of cells and synapses) for any vertebrate local circuit. Here we describe circuits in the cat retina that connect cones to the on‐beta ganglion cell. This cell type is important because on‐ and off‐beta cells contribute about 50% of the optic nerve fibres and the major retinal input to the striate cortex. Three adjacent on‐beta cells in the area centralis and their bipolar connections to cones were reconstructed from electron micrographs of 279 serial sections. The beta dendritic field is 34±2 μm in diameter and encompasses 35 cones. All of these cones connect to the beta cell via 14–17 bipolar cells. These bipolar cells were shown previously by cluster analysis to be of four types (b1‐b4); three of these types (b1′ b2 and b3) provided 97% of the bipolar contacts to the beta cell, in the ratio 4:2:1. On average, bipolar cells nearest the centre of the beta dendritic field contribute more synapses than those towards the edge, but the peaked distribution of bipolar synapses across the dendritic field is only slightly broader than the optical pointspread function of the cat's eye, and is narrower by half than the centre of the ganglion cell receptive field. This implies that the distribution of bipolar synapses across the beta cell dendritic field contributes little to the extent or shape of the receptive field. Since all three bipolar circuits connect to the same set of cones, they must carry the same spatial and chromatic information; they might convey different temporal frequencies. The numbers of bipolar synapses (mean ± SD = 154±8) and amacrine synapses (59±5) converging on three adjacent beta cells are remarkably constant (SD=±5% of the mean). Thus, as the circuits repeat locally, the fundamental design is accurately reproduced.
Acotiamide Hydrochloride (Z-338), a New Selective Acetylcholinesterase Inhibitor, Enhances Gastric Motility without Prolonging QT Interval in Dogs: Comparison with Cisapride, Itopride, and Mosapride

Acotiamide hydrochloride (acotiamide; N-[2-[bis(1-methylethyl) amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole-4-carboxamide monohydrochloride trihydrate, Z-338) has been reported to improve meal-related symptoms of functional dyspepsia in clinical studies. Here, we examined the gastroprokinetic effects of acotiamide and its antiacetylcholinesterase activity as a possible mechanism of action in conscious dogs. Acotiamide increased postprandial gastric motor activity in conscious dogs with chronically implanted force transducers and, like itopride, mosapride, and cisapride, exhibited gastroprokinetic activity in these dogs. Furthermore, acotiamide improved clonidine-induced hypomotility and delayed gastric emptying. Acotiamide-enhanced postprandial gastroduodenal motility was suppressed completely by pretreatment with atropine, a muscarinic receptor antagonist. In in vitro studies, acotiamide enhanced acetylcholine- but not carbachol-induced contractile responses of guinea pig gastric antrum strips. Moreover, like itopride and neostigmine, acotiamide inhibited recombinant human and canine stomach-derived acetylcholinesterase (AChE) activity in vitro. The mode of the AChE inhibitory action of acotiamide was selective and reversible. Unlike itopride or mosapride, acotiamide showed no affinity for dopamine D2 or serotonin 5-HT4 receptors. With regard to cardiovascular side effects, unlike cisapride, acotiamide did not affect myocardial monophasic action potential duration, QT interval, or corrected QT interval in anesthetized dogs. These results suggest that acotiamide stimulates gastric motility in vivo by inhibiting AChE activity without affecting QT interval. Acotiamide thus represents a beneficial new drug for the treatment of functional dyspepsia involving gastric motility dysfunction, with differences from other prokinetic agents.
Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group.

BACKGROUND Each year, clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We assessed whether rofecoxib, a selective inhibitor of cyclooxygenase-2, would be associated with a lower incidence of clinically important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis. METHODS We randomly assigned 8076 patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) and who had rheumatoid arthritis to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily. The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers). RESULTS Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib, as compared with 4.5 per 100 patient-years with naproxen (relative risk, 0.5; 95 percent confidence interval, 0.3 to 0.6; P<0.001). The respective rates of complicated confirmed events (perforation, obstruction, and severe upper gastrointestinal bleeding) were 0.6 per 100 patient-years and 1.4 per 100 patient-years (relative risk, 0.4; 95 percent confidence interval, 0.2 to 0.8; P=0.005). The incidence of myocardial infarction was lower among patients in the naproxen group than among those in the rofecoxib group (0.1 percent vs. 0.4 percent; relative risk, 0.2; 95 percent confidence interval, 0.1 to 0.7); the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups. CONCLUSIONS In patients with rheumatoid arthritis, treatment with rofecoxib, a selective inhibitor of cyclooxygenase-2, is associated with significantly fewer clinically important upper gastrointestinal events than treatment with naproxen, a nonselective inhibitor.
The Visual Semantic Web: Unifying Human and Machine Semantic Web Representations with Object-Process Methodology

The Visual Semantic Web (ViSWeb) paradigm enhances human accessibility to the current Semantic Web technology by enabling the visualization of knowledge. Arguing against the claim that humans and machines need to look at different knowledge representation formats, Object-Process Methodology (OPM) is shown to enable modeling of systems in a single graphic and textual model. ViSWeb provides for representation of knowledge over the Web in a unified way that caters to humans as well as machines. ViSWeb is developed as an OPM-based layer on top of XML/RDF/OWL to express knowledge visually and in natural language. Both the graphic and the textual representations are strictly equivalent. Being intuitive yet formal, they are not only understandable to humans, but are also amenable to computer processing. The advantages of the ViSWeb approach include equivalent graphic-text knowledge representation, visual navigability, semantic sentence interpretation, specification of system dynamics, and complexity management. The ability to use such bimodal knowledge representation that is both human understandable and machine processable is a major step forward in the evolution of the Semantic Web.
Accuracy and precision in quantitative fluorescence microscopy

The light microscope has long been used to document the localization of fluorescent molecules in cell biology research. With advances in digital cameras and the discovery and development of genetically encoded fluorophores, there has been a huge increase in the use of fluorescence microscopy to quantify spatial and temporal measurements of fluorescent molecules in biological specimens. Whether simply comparing the relative intensities of two fluorescent specimens, or using advanced techniques like Förster resonance energy transfer (FRET) or fluorescence recovery after photobleaching (FRAP), quantitation of fluorescence requires a thorough understanding of the limitations of and proper use of the different components of the imaging system. Here, I focus on the parameters of digital image acquisition that affect the accuracy and precision of quantitative fluorescence microscopy measurements.
A short conserved motif in ALYREF directs cap- and EJC-dependent assembly of export complexes on spliced mRNAs

The export of messenger RNAs (mRNAs) is the final of several nuclear posttranscriptional steps of gene expression. The formation of export-competent mRNPs involves the recruitment of export factors that are assumed to facilitate transport of the mature mRNAs. Using in vitro splicing assays, we show that a core set of export factors, including ALYREF, UAP56 and DDX39, readily associate with the spliced RNAs in an EJC (exon junction complex)- and cap-dependent manner. In order to elucidate how ALYREF and other export adaptors mediate mRNA export, we conducted a computational analysis and discovered four short, conserved, linear motifs present in RNA-binding proteins. We show that mutation in one of the new motifs (WxHD) in an unstructured region of ALYREF reduced RNA binding and abolished the interaction with eIF4A3 and CBP80. Additionally, the mutation impaired proper localization to nuclear speckles and export of a spliced reporter mRNA. Our results reveal important details of the orchestrated recruitment of export factors during the formation of export competent mRNPs.
Sterile neutrinos as dark matter.

The simplest model that can accommodate a viable nonbaryonic dark matter candidate is the standard electroweak theory with the addition of right-handed or sterile neutrinos. This model has been studied extensively in the context of the hot dark matter scenario. We reexamine this model and find that hot, warm, and cold dark matter are all possibilities. We focus on the case where sterile neutrinos are the dark matter. Since their only direct coupling is to left-handed or active neutrinos, the most efficient production mechanism is via neutrino oscillations. If the production rate is always less than the expansion rate, then these neutrinos will never be in thermal equilibrium. However, they may still play a significant role in the dynamics of the Universe and possibly provide the missing mass necessary for closure. We consider a single generation of neutrino fields ([nu][sub L], [nu][sub R]) with a Dirac mass, [mu], and a Majorana mass for the right-handed components only, M. For M [much gt] [mu] we show that the number density of sterile neutrinos is proportional to [mu][sup 2]/M so that the energy density today is independent of M. However M is crucial in determining the large scale structure of the Universe.more » In particular, M [approx equal] 0.1--1.0 key leads to warm dark matter and a structure formation scenario that may have some advantages over both the standard hot and cold dark matter scenarios. « less
Decoupling catalytic activity from biological function of the ATPase that powers lipopolysaccharide transport

Significance Gram-negative bacteria contain an unusual outer membrane that prevents the entry of most currently available antibiotics. This membrane contains a complex glycolipid, LPS, on the exterior. It is not understood how such a large molecule, which can contain hundreds of sugars and six fatty acyl chains, is transported across the cell envelope from its site of synthesis in the cytoplasmic membrane to the cell surface. Using a combination of genetics, biochemistry, and structural biology, we characterized residues in the protein that powers LPS transport to gain mechanistic insight into how ATP hydrolysis is coupled to the biological function of the transporter. These tools help us understand how to design antibiotics targeting this essential pathway. The cell surface of Gram-negative bacteria contains lipopolysaccharides (LPS), which provide a barrier against the entry of many antibiotics. LPS assembly involves a multiprotein LPS transport (Lpt) complex that spans from the cytoplasm to the outer membrane. In this complex, an unusual ATP-binding cassette transporter is thought to power the extraction of LPS from the outer leaflet of the cytoplasmic membrane and its transport across the cell envelope. We introduce changes into the nucleotide-binding domain, LptB, that inactivate transporter function in vivo. We characterize these residues using biochemical experiments combined with high-resolution crystal structures of LptB pre- and post-ATP hydrolysis and suggest a role for an active site residue in phosphate exit. We also identify a conserved residue that is not required for ATPase activity but is essential for interaction with the transmembrane components. Our studies establish the essentiality of ATP hydrolysis by LptB to power LPS transport in cells and suggest strategies to inhibit transporter function away from the LptB active site.
A dilated-CPU-consumption-based performance prediction for multi-core software routers

Network function virtualization (NFV) raises new possibilities for embedding data plane processing functions, e.g., firewalls, NAT, packet forwarding, etc., on commodity hardware. However, the advantages of flexibility, scalability and low cost of commodity hardware come at a price, such as resource over-provisioning, because the performance of softwarized network functions on shared resources is hardly predictable. This paper addresses the problem of performance prediction for multi-core software routers. Specifically, the performance prediction model is developed to predict the maximum throughput a multi-core software router can perform given assigned resources. Motivated by observations, we first mathematically analyze how many CPU cycles spent for packet forwarding in multi-core processing systems. Our analytical model based on cache contention can capture its nonlinear dilation scaled by the number of CPU cores-called dilated CPU consumption (DCC). We validate the accuracy of DCC with measured data, achieving error less than 8%. We then propose two performance prediction algorithms based on the DCC. The first algorithm relies on CPU utilization statistics (called DCC-u), while its simplified version (called sDCC) does not require CPU utilization statistics. Evaluation with measured data shows that the estimations of DCC-u has error margins less than 3% for a large packet size and 10% for a small packet size, while sDCC provides larger error than DCC-u. Remarkably, our both performance prediction algorithms yield more precise estimation than that of the benchmarking techniques.
Longitudinal Assessment of Critical Thinking in Pharmacy Students

Objectives. The purpose of this study was to describe changes in critical thinking ability and disposition over a 4-year Doctor of Pharmacy curriculum. Methods. Two standardized tests, the California Critical Thinking Skills Test (CCTST) and California Critical Thinking Dispositions Inventory (CCTDI) were used to follow the development of critical thinking ability and disposition during a 4-year professional pharmacy program. The tests were given to all pharmacy students admitted to the PharmD program at the College of Pharmacy of North Dakota State University (NDSU) on the first day of classes, beginning in 1997, and repeated late in the spring semester each year thereafter. Results. Increases in CCTST scores were noted as students progressed through each year of the curriculum, with a 14% total increase by graduation (P< 0.001). That the increase was from a testing effect is unlikely because students who took a different version at graduation scored no differently than students who took the original ver.
Plasma Ghrelin Concentrations Are Negatively Correlated With Urine Albumin-to-Creatinine Ratio in Newly Diagnosed Type 2 Diabetes

Background:Aging is associated with a decrease in appetite, energy intake and glucose tolerance. Experimental studies have suggested that ghrelin and obestatin play a role in glucose homeostasis and in the regulation of energy metabolism. However, few studies have been performed on the role of ghrelin and obestatin in middle-aged and old adults. Methods:In the present study, we investigated the plasma concentrations of ghrelin and obestatin in middle-aged (41–64 years) and old (65–76 years) subjects with newly diagnosed type 2 diabetes mellitus (NDD) and normal glucose tolerance (NGT). We also characterized the relationship among plasma ghrelin and obestatin levels and glucose/lipid metabolism. The fasting plasma ghrelin and obestatin concentrations were analyzed using enzyme immunoassay method. Results:Plasma obestatin concentrations in diabetic subjects were significantly lower than those in NGT subjects. Plasma ghrelin were negatively associated with fasting glucose, hemoglobin A1c, urine albumin-to-creatinine ratio (UACR) and positively correlated with high-density lipoprotein cholesterol. In addition, plasma obestatin level was correlated negatively with systolic blood pressure, triglycerides and total cholesterol. Furthermore, multiple regression analysis indicated that UACR was a significantly independent predictor of fasting plasma ghrelin levels. Conclusions:Collectively, ghrelin and obestatin levels may be markers reflecting glucose and lipid conditions in NDD. The lower ghrelin levels may be a potential indicator for renal dysfunction in patients with type 2 diabetes mellitus.
The Consequences of Marijuana Use During Pregnancy: A Review of the Human Literature

SUMMARY In spite of marijuana being the most widely used illegal drug among women of reproductive age there is a relative paucity of literature dealing with this topic. Of the data available, particularly in offspring beyond three years of age, most is generated by two ongoing cohort studies with very different populations. Both have reported similar findings. Up to approximately 3 years of age there appears to be very little impact upon the offspring. Beyond that age, in utero cannabis exposure does not impact upon standardized derived IQ scores but is negatively associated with attentional behavior and visual analysis/hypothesis testing. These findings are hypothesized as prenatal marijuana exposure having a negative influence on aspects of executive function-a “top-down,” multifaceted cognitive construct involved in organizing and integrating specific cognitive and output processes over a interval of time. The results and their interpretation are examined in terms of behavioral teratogenic effects (or .
Teaching the Design of Parallel Manipulators and Their Controllers Implementing MATLAB, Simulink, SimMechanics and CAD*

The teaching of parallel mechanisms and their controllers is a difficult task because of the complex mathematics that must be solved for the direct and indirect kinematics problems. In order to help students understand the kinematics and the dynamics of parallel manipulators and their controllers, we have designed a final-year robotics course based on MATLAB, Simulink and SimMechanics. Students are given specifications of the parallel manipulator that they must design, such as parameters of the DC motors to be used, the type of controller to be implemented, the number of degrees-of-freedom (DOF) of the developed robot, etc. Each group is then required to design a parallel manipulator of its choice in MATLAB, Simulink, SimMechanics and/or CAD. Finally, they are required to design the manipulator’s controller for simulation purposes. Some mechanical components of the best robot are rapid prototyped on the Dimension 3-D printer. The mathematical analysis of the best mechanism is then studied in detail. This is compared with the simulation of the integrated manipulator in MATLAB. This paper presents the mechanical design, analysis and controller design of the parallel manipulator that was developed in MATLAB.