Miracle-dz/UniFAR-FTUs huggingface dataset:
Bacterial Pulmonary Infection Proteinase-Activated Receptor 1 during Regulation of Neutrophilic Inflammation by Chambers

Neutrophils are key effector cells of the innate immune response to pathogenic bacteria, but excessive neutrophilic inflammation can be associated with bystander tissue damage. The mechanisms responsible for neutrophil recruitment to the lungs during bacterial pneumonia are poorly defined. In this study, we focus on the potential role of the major high-affinity thrombin receptor, proteinase-activated receptor 1 (PAR-1), during the development of pneumonia to the common lung pathogen Streptococcus pneumoniae. Our studies demonstrate that neutrophils were indispensable for controlling S. pneumoniae outgrowth but contributed to alveolar barrier disruption. We further report that intra-alveolar coagulation (bronchoalveolar lavage fluid thrombin–antithrombin complex levels) and PAR-1 immunostaining were increased in this model of bacterial lung infection. Functional studies using the most clinically advanced PAR-1 antagonist, SCH530348, revealed a key contribution for PAR-1 signaling in influencing neutrophil recruitment to lung airspaces in response to both an invasive and noninvasive strain of S. pneumoniae (D39 and EF3030) but that PAR-1 antagonism did not impair the ability of the host to control bacterial outgrowth. PAR-1 antagonist treatment significantly decreased pulmonary levels of IL-1b, CXCL1, CCL2, and CCL7 and attenuated alveolar leak. Ab neutralization studies further demonstrated a nonredundant role for IL-1b, CXCL1, and CCL7 in mediating neutrophil recruitment in response to S. pneumoniae infection. Taken together, these data demonstrate a key role for PAR-1 during S. pneumoniae lung infection that is mediated, at least in part, by influencing multiple downstream inflammatory mediators. L ower respiratory tract infections are a leading cause of morbidity and mortality and represent an enormous global healthcare burden (1). Infection with Streptococcus pneumoniae is the predominant cause of pneumonia and consequently one of the most common causes of death associated with infectious disease worldwide (2, 3). Bacterial pneumonia in humans is often accompanied by a pronounced inflammatory response , characterized by an acute phase reaction, the release of proinflammatory mediators, a heightened procoagulant state, and the recruitment of large numbers of neutrophils to the lung (4–6). This response is important for the control of bacterial infection (7–10), but excessive neutrophilic inflammation can also lead to bystander tissue damage, characterized by disruption of the al-veolar barrier, pulmonary edema, and severely compromised lung function (11, 12). The local activation of coagulation within the intra-alveolar compartment is a key feature of the pulmonary response to injury and infection (13). The major high-affinity thrombin receptor, proteinase-activated receptor 1 (PAR-1), has been shown to play a central role …
Predicting catheter ablation outcome in persistent atrial fibrillation using atrial dominant frequency and related spectral features

Pre-procedural atrial fibrillation dominant frequency (AFDF) has been reported to play a role as a predictor of catheter ablation (CA) outcome for the treatment of persistent atrial fibrillation (AF). The present study analyzes some spectral features of the atrial signal aimed at evaluating the quality of surface AFDF estimation and discusses their predictive power. First, automated extraction of surface atrial activity (AA) on pre-procedural 12-lead ECG recordings is performed by means of an independent component analysis (ICA) method. AFDF is then estimated by means of short-time Fourier analysis of the extracted atrial sources and simultaneous endocardial electrograms (EGM) used as reference. On a database of 20 patients in persistent AF undergoing CA, AFDF does not appear to play a role as a predictor of CA outcome at follow-up, neither on ECG nor on EGM recordings. The quality of surface AFDF estimation is assessed by means of the correlation coefficient r between surface and EGM AFDF, as well as the spectral concentration (SC) of the estimated atrial signal. It is shown that the quality of surface AFDF estimation is significantly lower for non-terminating CA procedures, both in terms of r and SC. The latter, in particular, seems to play a significant role in distinguishing terminating from non-terminating CA procedures and therefore in the non-invasive prediction of CA outcome.
Rising Incidence of Mucosal Melanoma of the Head and Neck in the United States

Background. While it is established that the incidence of cutaneous melanoma has risen over time in the United States, the incidence trend for mucosal melanoma of the head and neck (MMHN) is unknown. Methods. We used the Surveillance, Epidemiology, and End Results (SEER) database to determine incidence trends for MMHN from 1987 to 2009 in the United States. We determined annual percent change (APC) by weighted least squares and joinpoint regression analysis. Results. MMHN incidence increased from 1987 to 2009 (APC 2.4%; P < 0.01). Nasal cavity lesions increased in incidence (APC 2.7%; P < 0.01) over this duration, while the incidence of non-nasal cavity lesions remained stable. The highest rate of increase was in white females ages 55 to 84 (APC 5.1%; P = 0.01). Conclusions. The incidence of MMHN in the United States has been rising since 1987. This trend is driven primarily by increased incidence of nasal cavity melanomas.
Structural correlates of skilled performance on a motor sequence task

The brain regions functionally engaged in motor sequence performance are well-established, but the structural characteristics of these regions and the fiber pathways involved have been less well studied. In addition, relatively few studies have combined multiple magnetic resonance imaging (MRI) and behavioral performance measures in the same sample. Therefore, the current study used diffusion tensor imaging (DTI), probabilistic tractography, and voxel-based morphometry (VBM) to determine the structural correlates of skilled motor performance. Further, we compared these findings with fMRI results in the same sample. We correlated final performance and rate of improvement measures on a temporal motor sequence task (TMST) with skeletonized fractional anisotropy (FA) and whole brain gray matter (GM) volume. Final synchronization performance was negatively correlated with FA in white matter (WM) underlying bilateral sensorimotor cortex—an effect that was mediated by a positive correlation with radial diffusivity. Multi-fiber tractography indicated that this region contained crossing fibers from the corticospinal tract (CST) and superior longitudinal fasciculus (SLF). The identified SLF pathway linked parietal and auditory cortical regions that have been shown to be functionally engaged in this task. Thus, we hypothesize that enhanced synchronization performance on this task may be related to greater fiber integrity of the SLF. Rate of improvement on synchronization was positively correlated with GM volume in cerebellar lobules HVI and V—regions that showed training-related decreases in activity in the same sample. Taken together, our results link individual differences in brain structure and function to motor sequence performance on the same task. Further, our study illustrates the utility of using multiple MR measures and analysis techniques to specify the interpretation of structural findings.
Digitoxin-Induced Cytotoxicity in Cancer Cells Is Mediated through Distinct Kinase and Interferon Signaling Networks

Cardiac glycosides (e.g., digoxin, digitoxin) constitute a diverse family of plant-derived sodium pump inhibitors that have been in clinical use for the treatment of heart-related diseases (congestive heart failure, atrial arrhythmia) for many years. Recently though, accumulating in vitro and in vivo evidence highlight potential anticancer properties of these compounds. Despite the fact that members of this family have advanced to clinical trial testing in cancer therapeutics, their cytotoxic mechanism is not yet elucidated. In this study, we investigated the cytotoxic properties of cardiac glycosides against a panel of pancreatic cancer cell lines, explored their apoptotic mechanism, and characterized the kinetics of cell death induced by these drugs. Furthermore, we deployed a high-throughput kinome screening approach and identified several kinases of the Na-K-ATPase-mediated signal transduction circuitry (epidermal growth factor receptor, Src, pkC, and mitogen-activated protein kinases) as important mediators downstream of cardiac glycoside cytotoxic action. To further extend our knowledge on their mode of action, we used mass-spectrometry–based quantitative proteomics (stable isotope labeling of amino acids in cell culture) coupled with bioinformatics to capture large-scale protein perturbations induced by a physiological dose of digitoxin in BxPC-3 pancreatic cancer cells and identified members of the interferon family as key regulators of the main protein/protein interactions downstream of digitoxin action. Hence, our findings provide more in-depth information regarding the molecular mechanisms underlying cardiac glycoside-induced cytotoxicity. Mol Cancer Ther; 10(11); 2083–93. ©2011 AACR.
Molecular Evidence of Helicobacter cinaedi Organisms in Human Gastric Biopsy Specimens

ABSTRACT One hundred twenty-six urease-negative gastric biopsy specimens were evaluated for the presence of Helicobacter genus-specific 16S ribosomal DNA (rDNA) and H. pylori-specific glmM DNA sequences by PCR. The species specificity of the glmM PCR assay was demonstrated, as H. pylori was the only Helicobacter species that yielded the expected glmM amplicon. Most urease-negative specimens (118 of 126 specimens) lacked Helicobacter DNA. However, 8 of 126 urease-negative specimens contained Helicobacter 16S rDNA. In order to identify the Helicobacter species present in urease-negative gastric biopsy specimens, 16S rDNA amplicons were cloned and sequenced. Sequence comparisons were performed by analyses of the sequences in public sequence databases. Two samples contained 16S rDNA that was identified as H. cinaedi with 100% identity and that spanned approximately 400 bp (398 and 398 bp, respectively). In contrast, multiple differences (97% identity; 390 of 398 bp) were observed with H. pylori 16S rDNA in this region. This finding was verified by sequencing an overlapping 537-bp fragment within the 5′ portion of 16S rDNA. Although the clinical findings were consistent with H. pylori infection (e.g., duodenal ulcer disease), rapid urease testing and DNA sequence analyses suggested the presence of H. cinaedi organisms and the absence of H. pylori in two human antral biopsy specimens. This study represents the first report of an enteric urease-negative helicobacter in the human stomach. Although these organisms were previously associated with extragastric infections, the roles of these organisms in the pathogenesis of chronic gastritis or peptic ulcer disease remain unclear.
A novel randomized iterative strategy for aligning multiple protein sequences

The rigorous alignment of multiple protein sequences becomes impractical even with a modest number of sequences, since computer memory and time requirements increase as the product of the lengths of the sequences. We have devised a strategy to approach such an optimal alignment, which modifies the intensive computer storage and time requirements of dynamic programming. Our algorithm randomly divides a group of unaligned sequences into two subgroups, between which an optimal alignment is then obtained by a Needleman-Wunsch style of algorithm. Our algorithm uses a matrix with dimensions corresponding to the lengths of the two aligned sequence subgroups. The pairwise alignment process is repeated using different random divisions of the whole group into two subgroups. Compared with the rigorous approach of solving the n-dimensional lattice by dynamic programming, our iterative algorithm results in alignments that match or are close to the optimal solution, on a limited set of test problems. We have implemented this algorithm in a computer program that runs on the IBM PC class of machines, together with a user-friendly environment for interactively selecting sequences or groups of sequences to be aligned either simultaneously or progressively.
Structure and Function of Nucleoside Hydrolases from Physcomitrella patens and Maize Catalyzing the Hydrolysis of Purine, Pyrimidine, and Cytokinin Ribosides1[W]

Plant nucleoside N-ribohydrolases, which exist in two subclasses, play roles in cytokinin conversion and activation as well as in purine and pyrimidine metabolism. We present a comprehensive characterization of the nucleoside N-ribohydrolase (NRH) family in two model plants, Physcomitrella patens (PpNRH) and maize (Zea mays; ZmNRH), using in vitro and in planta approaches. We identified two NRH subclasses in the plant kingdom; one preferentially targets the purine ribosides inosine and xanthosine, while the other is more active toward uridine and xanthosine. Both subclasses can hydrolyze plant hormones such as cytokinin ribosides. We also solved the crystal structures of two purine NRHs, PpNRH1 and ZmNRH3. Structural analyses, site-directed mutagenesis experiments, and phylogenetic studies were conducted to identify the residues responsible for the observed differences in substrate specificity between the NRH isoforms. The presence of a tyrosine at position 249 (PpNRH1 numbering) confers high hydrolase activity for purine ribosides, while an aspartate residue in this position confers high activity for uridine. Bud formation is delayed by knocking out single NRH genes in P. patens, and under conditions of nitrogen shortage, PpNRH1-deficient plants cannot salvage adenosine-bound nitrogen. All PpNRH knockout plants display elevated levels of certain purine and pyrimidine ribosides and cytokinins that reflect the substrate preferences of the knocked out enzymes. NRH enzymes thus have functions in cytokinin conversion and activation as well as in purine and pyrimidine metabolism.
Imaging of urea using chemical exchange‐dependent saturation transfer at 1.5T

The purpose of this study was to screen for slow proton chemical exchange between water and kidney metabolites using a standard clinical 1.5‐T scanner. Imaging was performed using a fast spin‐echo sequence with a magnetization transfer (MT) preparation pulse train. Off‐resonance saturation ranging from ±50 to ±1000 Hz was used on urea and urine phantoms and normal human subjects imaged through the kidneys. The positive frequency was used as the control for each frequency pair. Results of frequency sweeps show an asymmetric MT effect peaking at approximately 100 Hz (∼︁1 ppm) for urea, urine, and renal parenchyma. Varying differences (5%–25%) occurred with different human subjects. Few differences were observed from phantom water or subject muscle tissue. Chemical exchange is detectable in the kidney near 1 ppm at 1.5 T, attributable to urea. This technique was used to produce in vivo distribution maps of this metabolite in vivo. J. Magn. Reson. Imaging 2000;12:745–748. © 2000 Wiley‐Liss, Inc.
Consolidating usability problems with novice evaluators

The process of consolidating usability problems (UPs) is an integral part of usability evaluation involving multiple users/analysts. However, little is known about the mechanism of this process and its effects on evaluation outcomes, which presumably influence how developers redesign the system of interest. We conducted an exploratory research study with ten novice evaluators to examine how they performed when merging UPs in the individual and collaborative setting and how they drew consensus. Our findings indicate that collaborative merging causes the absolute number of UPs to deflate, and concomitantly the frequency of certain UP types as well as their severity ratings to inflate excessively. It can be attributed to the susceptibility of novice evaluators to persuasion in a negotiation setting, and thus they tended to aggregate UPs leniently. Such distorted UP attributes may mislead the prioritization of UPs for fixing and thus result in ineffective system redesign.
Design of a touchless multipoint musical interface in a virtual studio environment

In this paper we describe a system for creating live musical expressions in a virtual studio environment. The underlying concept of this work is to provide casual and semi-professional users with a user experience that allow to easily create musical expressions without touch and visible feedback similar to the Theremin approach invented in in the early 20th century by Lev Theremin [26]. One or more performers stand in front of a studio camera inside a blue box and interact with an infrared-laser-based multi-touch device. The final TV image shows the performers interacting with a virtual screen, which is augmented in front of them, and background scenery that dynamically reacts to the music being produced. To overcome the problem of the performers not seeing this virtual screen in reality and yet being able to play melodic sequences, we use a special hexagonal pitch grid to facilitate the performer's awareness of this novel thereminlike virtual musical instrument.
Optimal Planning and Operation of Smart Grids with Electric Vehicle Interconnection

Connection of electric storage technologies to smartgrids will have substantial implications for building energy systems. Local storage will enable demand response. When connected to buildings, mobile storage devices such as electric vehicles (EVs) are in competition with conventional stationary sources at the building. EVs can change the financial as well as environmental attractiveness of on-site generation (e.g. PV or fuel cells). In order to examine the impact of EVs on building energy costs and CO2 emissions, a distributed-energy-resources adoption problem is formulated as a mixed-integer linear program with minimization of annual building energy costs or CO2 emissions and solved for 2020 technology assumptions. The mixedinteger linear program is applied to a set of 139 different commercial buildings in California and example results as well as the aggregated economic and environmental benefits are reported. Special constraints for the available PV, solar thermal, and EV parking lots at the commercial buildings are considered. The research shows that EV batteries can be used to reduce utility-related energy costs at the smart grid or commercial building due to arbitrage of energy between buildings with different tariffs. However, putting more emphasis on CO2 emissions makes stationary storage more attractive and stationary storage capacities increase while the attractiveness of EVs decreases. The limited availability of EVs at the commercial building decreases the attractiveness of EVs and if PV is chosen by the optimization, then it is mostly used to charge the stationary storage at the commercial building and not the EVs connected to the building.
Essential Role of Induced Nitric Oxide in the Initiation of the Inflammatory Response after Hemorrhagic Shock

Resuscitation from hemorrhagic shock induces profound changes in the physiologic processes of many tissues and activates inflammatory cascades that include the activation of stress transcriptional factors and upregulation of cytokine synthesis. This process is accompanied by acute organ damage (e.g., lungs and liver). We have previously demonstrated that the inducible nitric oxide synthase (iNOS) is expressed during hemorrhagic shock. We postulated that nitric oxide production from iNOS would participate in proinflammatory signaling. Using the iNOS inhibitor N6-(iminoethyl)-l-lysine or iNOS knockout mice we found that the activation of the transcriptional factors nuclear factor κB and signal transducer and activator of transcription 3 and increases in IL-6 and G-CSF messenger RNA levels in the lungs and livers measured 4 h after resuscitation from hemorrhagic shock were iNOS dependent. Furthermore, iNOS inhibition resulted in a marked reduction of lung and liver injury produced by hemorrhagic shock. Thus, induced nitric oxide is essential for the upregulation of the inflammatory response in resuscitated hemorrhagic shock and participates in end organ damage under these conditions.
Relation between low 50‐g glucose challenge test results and small‐for‐gestational‐age infants

There is no consensus opinion regarding a possible relation between low 50‐g glucose challenge test (GCT) results and small‐for‐gestational‐age infants (SGA). This study aimed to clarify the relation between low 50‐g GCT results and SGA, after adjusting for potential confounding factors, using a large clinical dataset.
How is radiating leg pain defined in randomized controlled trials of conservative treatments in primary care? A systematic review

Many terms exist to describe radiating leg pain or symptoms associated with back pain (e.g., sciatica or radiculopathy) and it appears that these terms are used inconsistently. We examined the terms used to describe, and the eligibility criteria used to define, radiating leg pain in randomized controlled trials of conservative treatments, and evaluated how the eligibility criteria compared to an international pain taxonomy. Eligible studies were identified from two systematic reviews and an updated search of their search strategy. Studies were included if they recruited adults with radiating leg pain associated with back pain. Two independent reviewers screened the studies and extracted data. Studies were grouped according to the terms used to describe radiating leg pain. Thirty‐one of the seventy‐seven included studies used multiple terms to describe radiating leg pain; the most commonly used terms were sciatica (60 studies) and disc herniation (19 studies). Most studies that used the term sciatica included pain distribution in the eligibility criteria, but studies were inconsistent in including signs (e.g., neurological deficits) and imaging findings. Similarly, studies that used other terms to describe radiating leg pain used inconsistent eligibility criteria between studies and to the pain taxonomy, except that positive imaging findings were required for almost all studies that used disc herniation to describe radiating leg pain. In view of the varying terms to describe, and eligibility criteria to define, radiating leg pain, consensus needs to be reached for each of communication and comparison between studies.
Arylamine N-Acetyltransferase Is Required for Synthesis of Mycolic Acids and Complex Lipids in Mycobacterium bovis BCG and Represents a Novel Drug Target

Mycolic acids represent a major component of the unique cell wall of mycobacteria. Mycolic acid biosynthesis is inhibited by isoniazid, a key frontline antitubercular drug that is inactivated by mycobacterial and human arylamine N-acetyltransferase (NAT). We show that an in-frame deletion of Mycobacterium bovis BCG nat results in delayed entry into log phase, altered morphology, altered cell wall lipid composition, and increased intracellular killing by macrophages. In particular, deletion of nat perturbs biosynthesis of mycolic acids and their derivatives and increases susceptibility of M. bovis BCG to antibiotics that permeate the cell wall. Phenotypic traits are fully complemented by introduction of Mycobacterium tuberculosis nat. We infer from our findings that NAT is critical to normal mycolic acid synthesis and hence other derivative cell wall components and represents a novel target for antituberculosis therapy. In addition, this is the first report of an endogenous role for NAT in mycobacteria.