Miracle-dz/UniFAR-FTUs huggingface dataset:
Tracheal intubation following training with the GlideScope® compared to direct laryngoscopy

Tracheal intubation using direct laryngoscopy has a high failure rate when performed by untrained medical personnel. This study compares tracheal intubation following direct laryngoscopy by inexperienced medical students when initially trained by using either the GlideScope®, a video assisted laryngoscope, or a rigid (Macintosh) laryngoscope. Forty‐two medical students with no previous experience in tracheal intubation were randomly divided into two equal groups to receive training with the GlideScope or with direct laryngoscopy. Subsequently, each medical student performed three consecutive intubations on patients with normal airways that were observed by a anaesthetist who was blinded to the training method. The rates of successful intubation were significantly higher in the Glidescope group after the first (48%), second (62%), and third (81%) intubations compared with the Macintosh group (14%, 14% and 33%; p = 0.043, 0.004 and 0.004, respectively). The mean (SD) times for the first, second, and third successful tracheal intubations were significantly shorter in the Glidescope group (59.3 (4.4) s, 56.6 (7.1) s and 50.1 (4.0) s) than the Macintosh group (70.7 (7.5) s, 73.7 (7.3) s and 67.6 (2.0) s; p = 0.006, 0.003 and 0.0001, respectively). Training with a video‐assisted device such as the GlideScope improves the success rate and time for tracheal intubation in patients with normal airways when this is performed by inexperienced individuals following a short training programme.
Role of antigen persistence and dose for CD4+ T-cell exhaustion and recovery

It is currently not understood how some chronic infections exhaust antigen-specific T cells over time and which pathogen components contribute to exhaustion. Here, we dissected the behavior of primed CD4+ T cells exposed to persistent antigen using an inducible transgenic mouse system that allowed us to control antigen presentation as the only experimental variable, independent of the persistent inflammation and disease progression that complicate infectious models. Moreover, this system restricted antigen presentation to dendritic cells (DCs) and avoided confounding B, CD8+ T, or innate cell responses. When antigen presentation was extended beyond the expansion phase, primed CD4+ T cells survived, but exhibited reduced memory functionality in terms of their proliferative capacity and cytokine expression potential. The effect was antigen dose and time dependent, not associated with increased PD-1 expression or reduced calcium influx, but impaired Jun phosphorylation in response to TCR engagement. Upon antigen removal, the cells regained the ability to proliferate, but remained unable to produce high levels of IL-2 and TNF-α. These data show that persistent antigen by itself rapidly induces a dysfunctional state in CD4+ T cells that is only partially reversible upon antigen removal. These findings have implications for vaccine optimization and for the possible reinvigoration of CD4+ T cells during chronic infection.
Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice

The metabolic syndrome is a clustering of risk factors of metabolic origin that increase the risk for cardiovascular disease and type 2 diabetes. A proposed central event in metabolic syndrome is a decrease in the amount of bioavailable nitric oxide (NO) from endothelial NO synthase (eNOS). Recently, an alternative pathway for NO formation in mammals was described where inorganic nitrate, a supposedly inert NO oxidation product and unwanted dietary constituent, is serially reduced to nitrite and then NO and other bioactive nitrogen oxides. Here we show that several features of metabolic syndrome that develop in eNOS-deficient mice can be reversed by dietary supplementation with sodium nitrate, in amounts similar to those derived from eNOS under normal conditions. In humans, this dose corresponds to a rich intake of vegetables, the dominant dietary nitrate source. Nitrate administration increased tissue and plasma levels of bioactive nitrogen oxides. Moreover, chronic nitrate treatment reduced visceral fat accumulation and circulating levels of triglycerides and reversed the prediabetic phenotype in these animals. In rats, chronic nitrate treatment reduced blood pressure and this effect was also present during NOS inhibition. Our results show that dietary nitrate fuels a nitrate–nitrite–NO pathway that can partly compensate for disturbances in endogenous NO generation from eNOS. These findings may have implications for novel nutrition-based preventive and therapeutic strategies against cardiovascular disease and type 2 diabetes.
Phosphorylation-independent dual-site binding of the FHA domain of KIF13 mediates phosphoinositide transport via centaurin α1

Phosphatidylinositol 3,4,5-triphosphate (PIP3) plays a key role in neuronal polarization and axon formation. PIP3-containing vesicles are transported to axon tips by the kinesin KIF13B via an adaptor protein, centaurin α1 (CENTA1). KIF13B interacts with CENTA1 through its forkhead-associated (FHA) domain. We solved the crystal structures of CENTA1 in ligand-free, KIF13B-FHA domain-bound, and PIP3 head group (IP4)-bound conformations, and the CENTA1/KIF13B-FHA/IP4 ternary complex. The first pleckstrin homology (PH) domain of CENTA1 specifically binds to PIP3, while the second binds to both PIP3 and phosphatidylinositol 3,4-biphosphate (PI(3,4)P2). The FHA domain of KIF13B interacts with the PH1 domain of one CENTA1 molecule and the ArfGAP domain of a second CENTA1 molecule in a threonine phosphorylation-independent fashion. We propose that full-length KIF13B and CENTA1 form heterotetramers that can bind four phosphoinositide molecules in the vesicle and transport it along the microtubule.
'Nobody Cares: The Challenge of Isolation in School-to-University Transition'

Drawing on a longitudinal study of a cohort of students moving from secondary school to university in Victoria in 1997, this paper considers perceptions of isolation and the identification of the university student as an ‘isolated learner’ among senior secondary students. Quantitative and qualitative research among these students in the first year of university suggest that these expectations of isolation are not always met, and that the quality and nature of their contact with university teachers does have an important affect upon their levels of satisfaction and commitment. The importance of contact, interest, approachability and care is supported by other studies, and suggests that institutions carefully examine and address the level and the nature of interaction between university teachers and learners, especially in the first year of study. The paper concludes with a brief discussion of some results of strategies to increase contact and show care in one university faculty.
An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis

The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) participates in the differentiation of FoxP3+ Treg, Tr1 cells, and IL-17–producing T cells (Th17). Most of our understanding on the role of AHR on the FoxP3+ Treg compartment results from studies using the toxic synthetic chemical 2,3,7,8-tetrachlorodibenzo-p-dioxin. Thus, the physiological relevance of AHR signaling on FoxP3+ Treg in vivo is unclear. We studied mice that carry a GFP reporter in the endogenous foxp3 locus and a mutated AHR protein with reduced affinity for its ligands, and found that AHR signaling participates in the differentiation of FoxP3+ Treg in vivo. Moreover, we found that treatment with the endogenous AHR ligand 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) given parenterally or orally induces FoxP3+ Treg that suppress experimental autoimmune encephalomyelitis. ITE acts not only on T cells, but also directly on dendritic cells to induce tolerogenic dendritic cells that support FoxP3+ Treg differentiation in a retinoic acid-dependent manner. Thus, our work demonstrates that the endogenous AHR ligand ITE promotes the induction of active immunologic tolerance by direct effects on dendritic and T cells, and identifies nontoxic endogenous AHR ligands as potential unique compounds for the treatment of autoimmune disorders.
Coexpression of potato type I and II proteinase inhibitors gives cotton plants protection against insect damage in the field

Potato type I and II serine protease inhibitors are produced by solanaceous plants as a defense mechanism against insects and microbes. Nicotiana alata proteinase inhibitor (NaPI) is a multidomain potato type II inhibitor (pin II) that is produced at high levels in the female reproductive tissues of the ornamental tobacco, Nicotiana alata. The individual inhibitory domains of NaPI target the major classes of digestive enzymes, trypsin and chymotrypsin, in the gut of lepidopteran larval pests. Although consumption of NaPI dramatically reduced the growth and development of a major insect pest, Helicoverpa punctigera, we discovered that surviving larvae had high levels of chymotrypsin activity resistant to inhibition by NaPI. We found a potato type I inhibitor, Solanum tuberosum potato type I inhibitor (StPin1A), was a strong inhibitor of the NaPI-resistant chymotrypsin activity. The combined inhibitory effect of NaPI and StPin1A on H. armigera larval growth in the laboratory was reflected in the increased yield of cotton bolls in field trials of transgenic plants expressing both inhibitors. Better crop protection thus is achieved using combinations of inhibitors in which one class of proteinase inhibitor is used to match the genetic capacity of an insect to adapt to a second class of proteinase inhibitor.
Corticospinal and spinal responses and adaptations from shortening and lengthening resistance training and subsequent detraining

Maximising strength and neurological adaptations to resistance training has long been sought to improve athletic performance and enhance clinical rehabilitation functional outcomes. In recent years, transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) have been applied to investigate changes in the central nervous system (CNS). Conventional resistance training programmes consist of shortening and lengthening muscle contractions and have been shown to have uniquely different motor control strategies; how this neurological control is modified during specific muscle contraction resistance training is unknown. Additionally, understanding the detraining process will assist in designing tapers for elite athletes and improve our knowledge of detraining and inactivity in other populations. The overall aim of the thesis was to determine the TMS and PNS responses to, and following, shortening and lengthening resistance exercise and subsequent detraining.
The mechanisms of a mammalian splicing enhancer

Abstract Exonic splicing enhancer (ESE) sequences are bound by serine & arginine-rich (SR) proteins, which in turn enhance the recruitment of splicing factors. It was inferred from measurements of splicing around twenty years ago that Drosophila doublesex ESEs are bound stably by SR proteins, and that the bound proteins interact directly but with low probability with their targets. However, it has not been possible with conventional methods to demonstrate whether mammalian ESEs behave likewise. Using single molecule multi-colour colocalization methods to study SRSF1-dependent ESEs, we have found that that the proportion of RNA molecules bound by SRSF1 increases with the number of ESE repeats, but only a single molecule of SRSF1 is bound. We conclude that initial interactions between SRSF1 and an ESE are weak and transient, and that these limit the activity of a mammalian ESE. We tested whether the activation step involves the propagation of proteins along the RNA or direct interactions with 3′ splice site components by inserting hexaethylene glycol or abasic RNA between the ESE and the target 3′ splice site. These insertions did not block activation, and we conclude that the activation step involves direct interactions. These results support a model in which regulatory proteins bind transiently and in dynamic competition, with the result that each ESE in an exon contributes independently to the probability that an activator protein is bound and in close proximity to a splice site.
In-Vivo and Postmortem Biomechanics of Abdominal Organs Under Compressive Loads: Experimental Approa

In order to provide realistic haptic (touch) feedback, simulators must incorporate accurate computational models of the in-vivo mechanical behavior of soft tissues. It is important to test tissues in surgically relevant ranges of applied force, duration, and deformation. In order to determine these ranges, a system known as the Blue DRAGON has been created that can track the motions of and the forces applied to surgical tools during live procedures. Thirty-one surgeons of varying skill were recorded performing three different surgical tasks. The mean force applied to the tool handles during tissue grasps was 8.52 N ± 2.77 N. Ninety-five percent of the handle angle frequency content was below 1.98 Hz ± 0.98 Hz. Average grasp time was 2.29 s ± 1.65 s, and 95 of all grasps observed were held for less than 8.86 s ± 7.06 s. The average maximum grasp time performed by surgeons during these tasks was 13.37 s ± 11.42 s. Using these values as design parameters, a computer-controlled, motorized endoscopic grasper (MEG) has been designed to obtain biomechanical properties of soft tissues in-vivo. The MEG uses a geared DC motor to drive a Babcock grasper using a cable-and-pulley mechanism. The motor is capable of producing the equivalent of 26.5 N of grasping force (470 kPa) by the end effector jaws. Two strain gage force-sensing beams are mounted in the partial pulley to accurately measure applied force. Computer-control is provided using a proportional-derivative position controller to command cyclic (up to 3 Hz) or step loadings. The MEG can be hand-held, weighs about 0.7 kg, and can be inserted into the body through standard endoscopic ports. The MEG has been calibrated and validated on linear springs with known stiffness. The MEG has been used to test 7 different porcine abdominal organs in-vivo and through 24 hours postmortem. Elastic and relaxation properties have been recorded and analyzed. Constitutive force-deformation relations have been fit to the elastic data, and stress relaxation functions have been fit to the stress-time data recorded during relaxation tests. An understanding of how the tissue properties and model parameters are influenced by time postmortem and loading condition has been obtained.
The analgesic efficacy of continuous wound instillation with ropivacaine after open hepatic surgery

The analgesic efficacy of continuous local anaesthetic wound instillation after open hepatic surgery was evaluated. Forty‐eight patients scheduled for elective liver surgery were assigned to receive either ropivacaine 0.25% or saline infusion at 4 ml.h−1 for 68 h via two multi‐orifice indwelling catheters placed within the musculo‐fascial layer before skin closure; plasma ropivacaine concentrations were measured during the infusion. Supplemental analgesia was provided by intravenous patient‐controlled analgesia morphine. Patients in the ropivacaine group had decreased mean (SD) total morphine consumption (58 (30) mg vs 86 (44) mg, p = 0.01) and less pain at rest as well as after spirometry at 4, 12, 24, 48 and 72 h postoperatively (p < 0.01). Forced vital capacity was reduced postoperatively in both groups, but the reduction was greater in the saline group at 12 and 24 h (p = 0.03). The mean plasma concentration of ropivacaine increased to 2.05 (0.78) μg. ml−1 at the point when the infusion was terminated.
Using mechanobiological mimicry of red blood cells to extend circulation times of hydrogel microparticles

It has long been hypothesized that elastic modulus governs the biodistribution and circulation times of particles and cells in blood; however, this notion has never been rigorously tested. We synthesized hydrogel microparticles with tunable elasticity in the physiological range, which resemble red blood cells in size and shape, and tested their behavior in vivo. Decreasing the modulus of these particles altered their biodistribution properties, allowing them to bypass several organs, such as the lung, that entrapped their more rigid counterparts, resulting in increasingly longer circulation times well past those of conventional microparticles. An 8-fold decrease in hydrogel modulus correlated to a greater than 30-fold increase in the elimination phase half-life for these particles. These results demonstrate a critical design parameter for hydrogel microparticles.
Conformational dynamics of bacteriophage T7 DNA polymerase and its processivity factor, Escherichia coli thioredoxin

Gene 5 of bacteriophage T7 encodes a DNA polymerase (gp5) responsible for the replication of the phage DNA. Gp5 polymerizes nucleotides with low processivity, dissociating after the incorporation of 1 to 50 nucleotides. Thioredoxin (trx) of Escherichia coli binds tightly (Kd = 5 nM) to a unique segment in the thumb subdomain of gp5 and increases processivity. We have probed the molecular basis for the increase in processivity. A single-molecule experiment reveals differences in rates of enzymatic activity and processivity between gp5 and gp5/trx. Small angle X-ray scattering studies combined with nuclease footprinting reveal two conformations of gp5, one in the free state and one upon binding to trx. Comparative analysis of the DNA binding clefts of DNA polymerases and DNA binding proteins show that the binding surface contains more hydrophobic residues than other DNA binding proteins. The balanced composition between hydrophobic and charged residues of the binding site allows for efficient sliding of gp5/trx on the DNA. We propose a model for trx-induced conformational changes in gp5 that enhance the processivity by increasing the interaction of gp5 with DNA.
Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

Cytochrome P450 enzymes play key roles in the metabolism of the majority of drugs. Improved models for prediction of likely metabolites will contribute to drug development. In this work, two possible metabolic routes (aromatic carbon oxidation and O-demethylation) of dextromethorphan are compared using molecular dynamics (MD) simulations and density functional theory (DFT). The DFT results on a small active site model suggest that both reactions might occur competitively. Docking and MD studies of dextromethorphan in the active site of P450 2D6 show that the dextromethorphan is located close to heme oxygen in a geometry apparently consistent with competitive metabolism. In contrast, calculations of the reaction path in a large protein model [using a hybrid quantum mechanical–molecular mechanics (QM/MM) method] show a very strong preference for O-demethylation, in accordance with experimental results. The aromatic carbon oxidation reaction is predicted to have a high activation energy, due to the active site preventing formation of a favorable transition-state structure. Hence, the QM/MM calculations demonstrate a crucial role of many active site residues in determining reactivity of dextromethorphan in P450 2D6. Beyond substrate binding orientation and reactivity of Compound I, successful metabolite predictions must take into account the detailed mechanism of oxidation in the protein. These results demonstrate the potential of QM/MM methods to investigate specificity in drug metabolism.
Mammalian endoplasmic reticulum stress sensor IRE1 signals by dynamic clustering

Accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), an intracellular signaling pathway that adjusts the protein folding capacity of the ER according to need. If homeostasis in the ER protein folding environment cannot be reestablished, cells commit to apoptosis. The ER-resident transmembrane kinase-endoribonuclease inositol-requiring enzyme 1 (IRE1) is the best characterized UPR signal transduction molecule. In yeast, Ire1 oligomerizes upon activation in response to an accumulation of misfolded proteins in the ER. Here we show that the salient mechanistic features of IRE1 activation are conserved: mammalian IRE1 oligomerizes in the ER membrane and oligomerization correlates with the onset of IRE1 phosphorylation and RNase activity. Moreover, the kinase/RNase module of human IRE1 activates cooperatively in vitro, indicating that formation of oligomers larger than four IRE1 molecules takes place upon activation. High-order IRE1 oligomerization thus emerges as a conserved mechanism of IRE1 signaling. IRE1 signaling attenuates after prolonged ER stress. IRE1 then enters a refractive state even if ER stress remains unmitigated. Attenuation includes dissolution of IRE1 clusters, IRE1 dephosphorylation, and decline in endoribonuclease activity. Thus IRE1 activity is governed by a timer that may be important in switching the UPR from the initially cytoprotective phase to the apoptotic mode.
Structural equation models and the quantification of behavior

Quantifying behavior often involves using variables that contain measurement errors and formulating multiequations to capture the relationship among a set of variables. Structural equation models (SEMs) refer to modeling techniques popular in the social and behavioral sciences that are equipped to handle multiequation models, multiple measures of concepts, and measurement error. This work provides an overview of latent variable SEMs. We present the equations for SEMs and the steps in modeling, and we provide three illustrations of SEMs. We suggest that the general nature of the model is capable of handling a variety of problems in the quantification of behavior, where the researcher has sufficient knowledge to formulate hypotheses.
Avaliação da efetividade da assistência pré-natal de uma Unidade de Saúde da Família em um município da Grande São Paulo

Visto la importancia de la calidad del cuidado prenatal en la reduccion de la morbidad y mortalidad materna y perinatal, este estudio tuvo como objetivo evaluar la calidad de la asistencia prestada a las mujeres embarazadas de bajo riesgo por medio de los indicadores de calidad preconizados por el Ministerio de la salud. Este es un estudio evaluativo, cuantitativo y retrospectivo realizado en un Servicio Prenatal de una Unidad de Salud de la Familia de un Municipio del Estado de Sao Paulo. Los resultados mostraron que el Programa de Salud de la Familia propicia asistencia prenatal de calidad y que el vinculo establecido entre los profesionales de la Unidad y los Agentes Comunitarios de la salud con las mujeres embarazadas es imprescindible para la adhesion de las mismas al programa de Asistencia Prenatal.
Endocannabinoid signaling directs differentiation of trophoblast cell lineages and placentation

In most mammals, placentation is critical for fetal development and pregnancy success. Exposure to marijuana during pregnancy has adverse effects, but whether the placenta is a target of cannabinoid/endocannabinoid signaling is not known. Using mice as a model system, we found that the endocannabinoid system is present in the ectoplacental cone and spongiotrophoblast cells. We also observed that aberrant endocannabinoid signaling confers premature trophoblast stem cell differentiation, and defective trophoblast development and invasion. These defects are reflected in retarded fetal development and compromised pregnancy outcome. Because the endocannabinoid system is conserved in mice and humans, our study suggests that endocannabinoid signaling is critical to placentation and pregnancy success in humans and implicates its potential significance in stem cell biology.