Miracle-dz/UniFAR-FTUs huggingface dataset:
Altered respiratory responses to hypoxia in mutant mice deficient in neuronal nitric oxide synthase

1 The role of endogenous nitric oxide (NO) generated by neuronal nitric oxide synthase (NOS‐1) in the control of respiration during hypoxia and hypercapnia was assessed using mutant mice deficient in NOS‐1. 2 Experiments were performed on awake and anaesthetized mutant and wild‐type control mice. Respiratory responses to varying levels of inspired oxygen (100, 21 and 12 % O2) and carbon dioxide (3 and 5 % CO2 balanced oxygen) were analysed. In awake animals, respiration was monitored by body plethysmograph along with oxygen consumption (VO2), CO2 production (VCO2) and body temperature. In anaesthetized, spontaneously breathing mice, integrated efferent phrenic nerve activity was monitored as an index of neural respiration along with arterial blood pressure and blood gases. Cyclic 3′,5′‐guanosine monophosphate (cGMP) levels in the brainstem were analysed by radioimmunoassay as an index of nitric oxide generation. 3 Unanaesthetized mutant mice exhibited greater respiratory responses during 21 and 12 % O2 than the wild‐type controls. Respiratory responses were associated with significant decreases in oxygen consumption in both groups of mice, and the magnitude of change was greater in mutant than wild‐type mice. Changes in CO2 production and body temperature, however, were comparable between both groups of mice. 4 Similar augmentation of respiratory responses during hypoxia was also observed in anaesthetized mutant mice. In addition, five of the fourteen mutant mice displayed periodic oscillations in respiration (brief episodes of increases in respiratory rate and tidal phrenic nerve activity) while breathing 21 and 12 % O2, but not during 100 % O2. The time interval between the episodes decreased by reducing inspired oxygen from 21 to 12 % O2. 5 Changes in arterial blood pressure and arterial blood gases were comparable at any given level of inspired oxygen between both groups of mice, indicating that changes in these variables do not account for the differences in the response to hypoxia. 6 Respiratory responses to brief hyperoxia (Dejours test) and to cyanide, a potent chemoreceptor stimulant, were more pronounced in mutant mice, suggesting augmented peripheral chemoreceptor sensitivity. 7 cGMP levels were elevated in the brainstem during 21 and 12 % O2 in wild‐type but not in mutant mice, indicating decreased formation of nitric oxide in mutant mice. 8 The magnitude of respiratory responses to hypercapnia (3 and 5 % CO2 balanced oxygen) was comparable in both groups of mice in the awake and anaesthetized conditions. 9 These observations suggest that the hypoxic responses were selectively augmented in mutant mice deficient in NOS‐1. Peripheral as well as central mechanisms contributed to the altered responses to hypoxia. These results support the idea that nitric oxide generated by NOS‐1 is an important physiological modulator of respiration during hypoxia.
Ultrafast and high-throughput N-glycan analysis for monoclonal antibodies

ABSTRACT Glycosylation is a critical attribute for development and manufacturing of therapeutic monoclonal antibodies (mAbs) in the pharmaceutical industry. Conventional antibody glycan analysis is usually achieved by the 2-aminobenzamide (2-AB) hydrophilic interaction liquid chromatography (HILIC) method following the release of glycans. Although this method produces satisfactory results, it has limited use for screening a large number of samples because it requires expensive reagents and takes several hours or even days for the sample preparation. A simple and rapid glycan analysis method was not available. To overcome these constraints, we developed and compared 2 ultrafast methods for antibody glycan analysis (UMAG) that involve the rapid generation and purification of glycopeptides in either organic solvent or aqueous buffer followed by label-free quantification using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Both methods quickly yield N-glycan profiles of test antibodies similar to those obtained by the 2-AB HILIC-HPLC method. In addition, the UMAG method performed in aqueous buffer has a shorter assay time of less than 15 min, and enables high throughput analysis in 96-well PCR plates with minimal sample handling. This method, the fastest, and simplest as reported thus far, has been evaluated for glycoprofiling of mAbs expressed under various cell culture conditions, as well as for the evaluation of antibody culture clones and various production batches. Importantly the method sensitively captured changes in glycoprofiles detected by traditional 2-AB HILIC-HPLC or HILIC-UPLC. The simplicity, high speed, and low cost of this method may facilitate basic research and process development for novel mAbs and biosimilar products.
Infection Site Concentrations: Their Therapeutic Importance and the Macrolide and Macrolide‐Like Class of Antibiotics

Much confusion exists over the pharmacodynamics of macrolides, azalides, and ketolides, as the concentration‐time profile for these agents is low relative to the minimum inhibitory concentration (MIC) of the pathogens for which they are used. Studies of respiratory tract infection have highlighted the importance of drug concentrations at the site of infection and have demonstrated a role for white blood cells in the delivery of drug to the infection site. Population mathematical modeling and Monte Carlo simulation have shown that the ability of macrolides, azalides, and ketolides to concentrate at the infection site has a considerable effect on microbial activity. Studies of the pharmacodynamics of these agents in animal models have centered on the mouse thigh model; however, the suitability of this model for investigation of respiratory tract infections for macrolides and macrolide‐like drugs is questionable. Comparison of the mouse thigh model with the mouse lung model shows immediate discrepancies, such as a need for higher area under the concentration‐time curve (AUC):MIC ratios in the mouse thigh. There are obvious failings in the use of a thigh model, as it does not take into account the accumulation of white blood cells in the epithelial lining fluid and therefore ignores the impact of white blood cell delivery to the site of infection and release of significant amounts of drug during phagocytosis. Ultimately, whereas the mouse pneumonia model is useful in identifying pharmacodynamically linked variables and the magnitude of variable required for a successful microbiologic outcome, extrapolation to human dosing must involve the use of human epithelial lining fluid penetration data.
Improved 3D phase contrast MRI with off‐resonance corrected dual echo VIPR

Phase contrast (PC) magnetic resonance imaging with a three‐dimensional, radially undersampled acquisition allows for the acquisition of high resolution angiograms and velocimetry in dramatically reduced scan times. However, such an acquisition is sensitive to blurring and artifacts from off‐resonance and trajectory errors. A dual‐echo trajectory is proposed with a novel trajectory calibration from prescan data coupled with a multi‐frequency reconstruction to correct for these errors. Comparisons of phantom data and in vivo results from volunteer, and patients with arteriovenous malformations patients are presented with and without these corrections and show significant improvement of image quality when both corrections are applied. The results demonstrate significantly improved visualization of vessels, allowing for highly accelerated PC acquisitions without sacrifice in image quality. Magn Reson Med 60:1329–1336, 2008. © 2008 Wiley‐Liss, Inc.
Sickness absence frequency among women working in hospital care.

BACKGROUND Frequent short sickness absences result in understaffing and interfere with work processes. We need more knowledge about factors associated with this type of absence. AIMS To investigate associations between the frequency of previous sickness absence and self-reported perceptions of health and work. METHODS Cross-sectional study of female hospital care workers in which health, work characteristics and coping styles were assessed by questionnaire and linked to the number of sickness absence episodes recorded in the preceding 5 years using negative binomial regression analysis for counts distinguishing between short (1-7 days) and long (>7 days) episodes of absence after adjusting for age and duration of employment in December 2007 and hours worked between 2003 and 2007. RESULTS Of 350 women employed for at least 5 years, 237 (68%) answered the questionnaire. The hours worked over the 5 year period [rate ratio (RR) = 1.2] and problem solving coping style score (RR = 1.1) were positively associated with the number of short sickness absence episodes. Age (RR = 0.8) and good general health (RR = 0.7) were inversely related to the number of both short and long episodes. Self-reported mental health and work characteristics were not shown to be related to the frequency of sickness absence. CONCLUSIONS Hours worked, problem-solving coping style, age and general health showed associations with the frequency of previous sickness absence among women who had worked at least 5 years in health care. Future prospective studies on the frequency of sickness absence should consider the impact of these factors further.
Guanine Nucleotides, Including GMP, Antagonize Kainate Responses in Xenopus Oocytes Injected with Chick Cerebellar Membranes

Abstract: Injection of chick cerebellar membranes, rich in kainate binding sites, into Xenopus oocytes resulted in the structural integration of chick membrane patches into the oocyte plasma membrane that could be easily identified by specific immunofluorescent staining. Application of kainate to the oocyte perfusion medium, under voltage‐clamp conditions, induced dose‐dependent (EC50= 87 ± 14 μM) inward currents, confirming the functional incorporation to the oocyte of kainate‐driven channels. Responses to kainate were consistently nondesensitizing and strongly potentiated by cyclothiazide, suggesting the selective involvement of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA)‐preferring receptors. Binding experiments with (S)‐[3H]AMPA confirmed the presence in the chick membrane preparation of low‐affinity AMPA receptors (KD= 278 nM) amounting to <2% of the total population of kainate binding sites. A tenfold concentration of guanine nucleotides, with different degrees of phosphorylation, blocked the responses to 100 μM kainate by ∼90%. In the case of GMP, additional concentration‐inhibition studies yielded an IC50 of 180 ± 11 μM. Our results illustrate the apparent failure of kainate‐binding proteins to form functional channels, even when maintaining their own native membrane environment, and confirm the antagonistic behavior of guanine nucleotides, including GMP, toward glutamate receptors, in agreement with previous results of ligand‐binding experiments and, more interestingly, with the marked neuroprotective effects of some guanine nucleotides in different excitotoxicity experimental paradigms.
Pseudomonas aeruginosa autoinducer modulates host cell responses through calcium signalling

The opportunistic pathogen Pseudomonas aeruginosa utilizes a cell density‐dependent signalling phenomenon known as quorum sensing (QS) to regulate several virulence factors needed for infection. Acylated homoserine lactones, or autoinducers, are the primary signal molecules that mediate QS in P. aeruginosa. The autoinducer N‐3O‐dodecanoyl‐homoserine lactone (3O‐C12) exerts effects on mammalian cells, including upregulation of pro‐inflammatory mediators and induction of apoptosis. However, the mechanism(s) by which 3O‐C12 affects mammalian cell responses is unknown. Here we report that 3O‐C12 induces apoptosis and modulates the expression of immune mediators in murine fibroblasts and human vascular endothelial cells (HUVEC). The effects of 3O‐C12 were accompanied by increases in cytosolic calcium levels that were mobilized from intracellular stores in the endoplasmic reticulum (ER). Calcium release was blocked by an inhibitor of phospholipase C, suggesting that release occurred through inositol triphosphate (IP3) receptors in the ER. Apoptosis, but not immunodulatory gene activation, was blocked when 3O‐C12‐exposed cells were co‐incubated with inhibitors of calcium signalling. This study indicates that 3O‐C12 can activate at least two independent signal transduction pathways in mammalian cells, one that involves increases in intracellular calcium levels and leads to apoptosis, and a second pathway that results in modulation of the inflammatory response.
GPU Acceleration of Algebraic Multigrid Preconditioners for Discrete Elliptic Field Problems

The simulation of coupled electromagnetic/thermal problems with high resolution requires efficient numerical schemes. High-performance computing languages like CUDA help in unlocking the massively parallel capabilities of graphic processor units (GPUs) to accelerate those calculations. This reduces the time needed to solve real-world problems. In this paper, the speedup is discussed, which is obtained using NVIDIA's recently presented Kepler architecture as well as by GPU-accelerated algebraic multigrid preconditioners. In particular, extended memory allows for the solving of larger problems with more degrees of freedom without swapping. We discuss a new host-based multigrid setup for GPU-accelerated iterative solvers.
Nuclear NF-κB/p65 expression and response to neoadjuvant chemotherapy in breast cancer

Aims To evaluate the clinicopathological associations and predictive value of the transcription factor NF-κB in a large series of breast cancer patients treated with neoadjuvant chemotherapy. Methods A retrospective search of a prospectively maintained database was performed to identify patients. Immunohistochemistry was used to assess the p65 subunit of NF-κB, using nuclear staining as a surrogate of activation. Results Nuclear NF-κB expression was found in 26.3% (35/133) of cases. Nuclear NF-κB staining was associated with high histological grade (p=0.05), oestrogen receptor (ER) negativity (p=0.01) and higher Ki67 index (p=0.002). Patients with nuclear NF-κB staining had a higher pathological complete response (pCR) rate than those without (26.5% vs 6.0% respectively, p=0.004); there was no significant association with clinical response or outcome. In an exploratory hypothesis-generating analysis, in the ER+/HER2− subgroup (n=43) a significantly lower clinical response rate was observed in those with nuclear NF-κB staining compared with those who had no nuclear NF-κB staining (14.3% vs 61.0%, p=0.038). There were no pCRs in ER+/ HER2− tumours. Conclusions Nuclear NF-κB expression is associated with ER negativity, higher Ki67 index and tumour grade. It was also found to be significantly associated with increased pCR but not clinical response to neoadjuvant chemotherapy.
Design and evaluation of a haptically enable virtual environment for object assembly training

Virtual training systems are attracting paramount attention from the manufacturing industries due to their potential advantages over the conventional training practices. Significant cost savings can be realized due to the shorter times for the development of different training-scenarios as well as reuse of existing designed engineering (math) models. This paper presents a newly developed virtual environment (VE) for training of procedure tasks i.e. object assembly. Unlike existing VE systems, the presented idea tries to imitate real physical training scenarios by providing comprehensive user interaction, constrained within the physical limitations of the real world. These physical constrains are imposed by the haptics devices in the virtual environment. As a result, in contrast to the existing VE systems that are capable of providing knowledge generally about assembly sequences only, the proposed system helps in cognitive learning and procedural skill development due to its high physically interactive nature. In addition a novel evaluation framework has also been proposed to evaluate system efficacy through a large scale of user-testing, which is often been neglected by design experts in the field of VEs. Results confirm the practical significance of evaluating a VE design by involving sample of real and representative users through the effective discovery of critical usability problems and system deficiencies. Results also indicate benefits of collecting multimodal information for accurate and comprehensive assessment of system efficacy. Evaluation results and improvement of existing design are also presented.
Histopathologic classification of small cell lung cancer changing concepts and terminology

Considerable attention has been devoted to the diagnosis of small cell lung carcinoma (SCLC) and its subtypes. In the literature contradictory opinions have been published concerning the clinical implications of subtyping, largely because of the different criteria used by different pathologists. This article is a consensus report by the Pathology Committee of the International Association for the Study of Lung Cancer. The following classification of SCLC is recommended: (1) Small cell carcinoma. This subtype includes most of the tumors previously included in the oat cell and intermediate subtypes. More than 90% of untreated SCLC fall into this category. (2) Mixed small cell/large cell carcinoma. This subtype, which may be associated with a poor prognosis and response to therapy, contains a spectrum of cell types ranging from typical SCLC to larger cells having prominent nucleoli and resembling large cell carcinoma. (3) Combined small cell carcinomas. Typical SCLC elements are intimately admixed with areas of differentiated squamous cell or adenocarcinoma. This simplified classification of SCLC will facilitate uniformity in the diagnosis and further our understanding of the clinical significance of the rarer SCLC with variant morphologies.
Effects of the calcium antagonist gallopamil (D600) upon excitation‐contraction coupling in toe muscle fibres of the frog.

1. The effects of the Ca2+ antagonist gallopamil (D600) upon force development in short skeletal muscle fibres (m. lumbricalis digiti IV) of the frog were investigated under voltage‐clamp control, using two flexible internal micro‐electrodes (temperature = 6‐7 degrees C). 2. In the presence of 5‐100 microM‐gallopamil muscle fibres developed one normal phasic contracture when they were depolarized from a holding potential of ‐90 to 0 mV. Subsequent depolarizations caused no mechanical response (paralysis). However, the ability to contract could be restored by hyperpolarizing the membrane to potentials between ‐120 and ‐150 mV. 3. In the absence of gallopamil, mechanical refractoriness could be fully reversed within 5‐7 s by repolarizing the fibre from 0 to ‐120 mV. In the presence of 100 microM‐gallopamil, no detectable restoration occurred within the first minute at ‐120 mV, and 45 to 100% of maximum force was eventually reached after 6 min of restoration. 4. The potential V at which the 'steady state' 50% of maximum force of a refractory fibre was restored shifted from ‐51 mV under normal conditions to ‐83 and ‐90 mV in the presence of 5 and 100 microM‐gallopamil, respectively. 5. Paralysis in the presence of gallopamil and recovery from paralysis during hyperpolarization could also be observed when 2 mM‐Cd2+ was applied to the external solution, i.e. when most Ca2+ channels in the T‐tubular system were blocked. 6. Gallopamil shifted the threshold for activation of force to more negative potentials. Fibres developed force when they were depolarized to membrane potentials between ‐60 and ‐80 mV, whereby a fast phase of activation was followed by a slower one. Upon repolarization relaxation likewise occurred in a fast and a slow phase. 7. High concentrations of gallopamil (greater than 500 microM) caused a slowly developing contracture, independent of membrane potential (‐90 or 0 mV). 8. It is proposed that gallopamil binds to a receptor at the force‐controlling system in the T‐tubular membrane (potential sensor) with a high affinity in the depolarized state and a lower affinity at negative potentials. Therefore association of gallopamil mainly leads to stabilization of the inactive state (paralysis) but can also stabilize the active state.
Binary neural network with 16 Mb RRAM macro chip for classification and online training

On-chip implementation of large-scale neural networks with emerging synaptic devices is attractive but challenging, primarily due to the pre-mature analog properties of today's resistive memory technologies. This work aims to realize a large-scale neural network using today's available binary RRAM devices for image recognition. We propose a methodology to binarize the neural network parameters with a goal of reducing the precision of weights and neurons to 1-bit for classification and <8-bit for online training. We experimentally demonstrate the binary neural network (BNN) on Tsinghua's 16 Mb RRAM macro chip fabricated in 130 nm CMOS process. Even under finite bit yield and endurance cycles, the system performance on MNIST handwritten digit dataset achieves ∼96.5% accuracy for both classification and online training, close to ∼97% accuracy by the ideal software implementation. This work reports the largest scale of the synaptic arrays and achieved the highest accuracy so far.
Intrapartum synthetic oxytocin reduce the expression of primitive reflexes associated with breastfeeding.

AIM Several synthetic peptide manipulations during the time surrounding birth can alter the specific neurohormonal status in the newborn brain. This study is aimed at assessing whether intrapartum oxytocin administration has any effect on primitive neonatal reflexes and determining whether such an effect is dose-dependent. MATERIALS AND METHODS A cohort prospective study was conducted at a tertiary hospital. Mother-infant dyads who received intrapartum oxytocin (n=53) were compared with mother-infant dyads who did not receive intrapartum oxytocin (n=45). Primitive neonatal reflexes (endogenous, antigravity, motor, and rhythmic reflexes) were quantified by analyzing videotaped breastfeeding sessions in a biological nurturing position. Two observers blind to the group assignment and the oxytocin dose analyzed the videotapes and assesed the newborn's state of consciousness according to the Brazelton scale. RESULTS The release of all rhythmic reflexes (p=0.01), the antigravity reflex (p=0.04), and total primitive neonatal reflexes (p=0.02) in the group exposed to oxytocin was lower than in the group not exposed to oxytocin. No correlations were observed between the dose of oxytocin administered and the percentage of primitive neonatal reflexes released (r=0.03; p=0.82). CONCLUSIONS Intrapartum oxytocin administration might inhibit the expression of several primitive neonatal reflexes associated with breastfeeding. This correlation does not seem to be dose-dependent.
Perceived Ethical Performance of News Media: Regaining Public Trust and Encouraging News Participation

ABSTRACT As news media face declining levels of trust, research has suggested that partisans may differ in their views of news media. Depending on their ideological positions, partisans may have different perceptions of how faithfully news media adhere to journalistic norms. This study explores the intersections of ideology, perceived ethical performance of news media, trust in news media, and news participatory behaviors. Our analyses of data from a national representative survey of 452 respondents show that liberals are more likely than conservatives to perceive that news media operate ethically. More important, we found that liberals trust news media more than conservatives because of this evaluation. Our results also suggest that participation in news is positively related to ethical performance evaluations, which partly account for different levels of participation between conservatives and liberals. Implications for regaining media trust and encouraging participatory practices are discussed.