bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of compression parameters on mechanical behavior of mozzarella cheese
Authors: Fogaça Davi Novaes Ladeia , da Silva William Soares , Rodrigues Luciano Brito
Published: December 2016

Studies on the interaction between direction and degree of compression in the Texture Profile Analysis (TPA) of cheeses are limited. For this reason the present study aimed to evaluate the mechanical properties of Mozzarella cheese by TPA at different compression degrees (65, 75, and 85%) and directions (axes X, Y, and Z). Data obtained were compared in order to identify possible interaction between both factors. Compression direction did not affect any mechanical variable, or rather, the cheese had an isotropic behavior for TPA. Compression degree had a significant influence (p < 0.05) on TPA responses, excepting for chewiness TPA (N), which remained constant. Data from texture profile were adjusted to models to explain the mechanical behavior according to the compression degree used in the test. The isotropic behavior observed may be result of differences in production method of Mozzarella cheese especially on stretching of cheese mass.

Practical applications

Texture Profile Analysis (TPA) is a technique largely used to assess the mechanical properties of food, particularly cheese. The precise choice of the instrumental test configuration is essential for achieving results that represent the material analyzed. The method of manufacturing is another factor that may directly influence the mechanical properties of food. This can be seen, for instance, in stretched curd cheese, such as Mozzarella. Knowledge on such mechanical properties is highly relevant for food industries due to the mechanical resistance in piling, pressing, manufacture of packages, and food transport, or to melting features presented by the food at high temperatures in preparation of several foods, such as pizzas, snacks, sandwiches, and appetizers.
Altered distribution of adrenergic constrictor responses contributes to skeletal muscle perfusion abnormalities in metabolic syndrome
Authors: Lemaster Kent , Jackson Dwayne , Welsh Donald G. , Brooks Steven D. , Chantler Paul D. , Frisbee Jefferson C.
Published: December 2016

Purpose

Although studies suggest elevated adrenergic activity paralleling metabolic syndrome in OZRs, the moderate hypertension and modest impact on organ perfusion question the multi‐scale validity of these data.

Methods

To understand how adrenergic function contributes to vascular reactivity in OZR, we utilized a multi‐scale approach to investigate pressure responses, skeletal muscle blood flow, and vascular reactivity following adrenergic challenge.

Results

For OZR, adrenergic challenge resulted in increased pressor responses vs LZRs, mediated via α1 receptors, with minimal contribution by either ROS or NO bioavailability. In situ gastrocnemius muscle of OZR exhibited blunted functional hyperemia, partially restored with α1 inhibition, although improved muscle performance and VO2 required combined treatment with TEMPOL. Within OZR in situ cremaster muscle, proximal arterioles exhibited a more heterogeneous constriction to adrenergic challenge, biased toward hyperresponsiveness, vs LZR. This increasingly heterogeneous pattern was mirrored in ex vivo arterioles, mediated via α1 receptors, with roles for ROS and NO bioavailability evident in hyperresponsive vessels only.

Conclusions

These results support the central role of the α1 adrenoreceptor for augmented pressor responses and elevations in vascular resistance, but identify an increased heterogeneity of constrictor reactivity in OZR that is presently of unclear purpose.
Does schema therapy change schemas and symptoms? A systematic review across mental health disorders
Authors: Taylor Christopher D. J. , Bee Penny , Haddock Gillian
Published: December 2016

Purpose

Schema therapy was first applied to individuals with borderline personality disorder (BPD) over 20 years ago, and more recent work has suggested efficacy across a range of disorders. The present review aimed to systematically synthesize evidence for the efficacy and effectiveness of schema therapy in reducing early maladaptive schema (EMS) and improving symptoms as applied to a range of mental health disorders in adults including BPD, other personality disorders, eating disorders, anxiety disorders, and post‐traumatic stress disorder.

Methods

Studies were identified through electronic searches (EMBASE, PsycINFO, MEDLINE from 1990 to January 2016).

Results

The search produced 835 titles, of which 12 studies were found to meet inclusion criteria. A significant number of studies of schema therapy treatment were excluded as they failed to include a measure of schema change. The Clinical Trial Assessment Measure was used to rate the methodological quality of studies. Schema change and disorder‐specific symptom change was found in 11 of the 12 studies.

Conclusions

Schema therapy has demonstrated initial significant results in terms of reducing EMS and improving symptoms for personality disorders, but formal mediation analytical studies are lacking and rigorous evidence for other mental health disorders is currently sparse.

Practitioner points

First review to investigate whether schema therapy leads to reduced maladaptive schemas and symptoms across mental health disorders.

Limited evidence for schema change with schema therapy in borderline personality disorder (BPD), with only three studies conducting correlational analyses.

Evidence for schema and symptom change in other mental health disorders is sparse, and so use of schema therapy for disorders other than BPD should be based on service user/patient preference and clinical expertise and/or that the theoretical underpinnings of schema therapy justify the use of it therapeutically.

Further work is needed to develop the evidence base for schema therapy for other disorders.
Neuromuscular responses of the plantar flexors to whole‐body vibration
Authors: Harwood B. , Scherer J. , Brown R. E. , Cornett K. M. D. , Kenno K. A. , Jakobi J. M.
Published: December 2016

Enhanced physical performance following whole‐body vibration (WBV) has been attributed to increased muscle activity; however, few studies have measured the mechanisms underlying these changes. The objective of this study was to measure the responsiveness of the Ia pathway as well as contractile properties in 16 young adults (24±2 years, eight men, eight women) following repeated bouts of acute WBV (45 Hz, 2 mm). Hoffman reflexes (H‐reflex), compound muscle action potentials (M‐wave), and twitch contractile properties were measured prior to and immediately following five 1‐minute WBV exposures, and at 3, 5, 10, and 20 minute post‐WBV. M‐wave and H‐reflex amplitudes decreased by 8% (P<.001) and by 46% (P<.05), respectively, whereas peak twitch torque decreased by 9% (P<.01) and rate of twitch torque development slowed 8% (P<.05). Percent voluntary activation and maximal plantar flexor torque were unchanged as a consequence of WBV (P>.05). In response to acute WBV, the root mean square of the soleus electromyography signal (EMGRMS) increased by 8%, while the EMGRMS of the lateral gastrocnemius increased by 3% (P<.05). These data indicate that the responsiveness of the Ia pathway is diminished and contractile function is impaired immediately following WBV, and that the neural mechanisms underlying improved performance following WBV lie in alternative hypotheses possibly involving spindle disfacilitation or Golgi afferent modulation.
The muscle biopsy technique. Historical and methodological considerations
Authors: Ekblom B.
Published: December 2016

The muscle biopsy method is an important tool for clinical and scientific work. In this study, the two most used instruments, the Bergström needle and the Well‐Blakesley conchotome, are described. The technique of using those instruments, risks, and other considerations are discussed. Finally, a few consequences and the error of the method for determining muscle fiber type, fiber area, substrates, and metabolites are presented.
The role of CD4 cell count as discriminatory measure to guide chemoprophylaxis against Pneumocystis jirovecii pneumonia in human immunodeficiency virus‐negative immunocompromised patients: A systematic review
Authors: Messiaen Peter E. , Cuyx Senne , Dejagere Tom , van der Hilst Jeroen C.
Published: December 2016

Background

In recent years, the incidence of Pneumocystis jirovecii pneumonia (PJP) has increased in immunocompromised patients without human immunodeficiency virus (HIV) infection. Chemoprophylaxis with trimethoprim‐sulfamethoxazole (TMP‐SMX) is highly effective in preventing PJP in both HIV‐positive and ‐seronegative patients. In HIV‐positive patients, the risk of PJP is strongly correlated with decreased CD4 cell count. The role of CD4 cell count in the pathogenesis of PJP in non‐HIV immunocompromised patients is less well studied. For most immunosuppressive conditions, no clear guidelines indicate whether to start TMP‐SMX.

Method

We conducted a systematic literature review with the aim to provide a comprehensive overview on the role of CD4 cell counts in managing the risk of PJP in HIV‐seronegative patients.

Results

Of the 63 individual studies retrieved, 14 studies report on CD4 cell counts in a variety of immunosuppressive conditions. CD4 cell count were <200/μL in 73.1% of the patients.

Conclusion

CD4 cell count <200/μL is a sensitive biomarker to identify non‐HIV immunocompromised patients who are at risk for PJP. Measuring CD4 cell counts could help clinicians identify patients who may benefit from TMP‐SMX prophylaxis.
Early diagnosis of Ehrlichia ewingii infection in a lung transplant recipient by peripheral blood smear
Authors: Regunath Hariharan , Rojas‐Moreno Christian , Olano Juan P. , Hammer Richard D. , Salzer William
Published: December 2016

Ehrlichiosis in lung transplant (LT) recipients is associated with severe outcomes. Ehrlichia ewingii is a less frequent cause of symptomatic ehrlichiosis, characterized by cytoplasmic inclusions (morulae) within circulating neutrophils. We report a case of E. ewingii infection in an LT recipient diagnosed promptly by blood smear exam and confirmed with molecular studies.
Additional intraarticular tranexamic acid further reduced postoperative blood loss compared to intravenous and topical bathed tranexamic acid in total hip arthroplasty: a retrospective sequential series study
Authors: Nakura Nariaki , Hirakawa Kazuo , Takayanagi Satoshi , Saito Akira , Tsuji Koji , Tamaki Yasunobu , Ochiai Shunsuke , Mihara Masahiko
Published: December 2016

BACKGROUND

Topical tranexamic acid (TXA) administration has been described to be effective in decreasing blood loss in total hip arthroplasty (THA). The aim of this retrospective study was to evaluate whether topical intraarticular TXA administration in addition to intravenous (IV) and topical bathed TXA further reduces blood loss in THA patients.

STUDY DESIGN AND METHODS

Four‐hundred patients were enrolled in this sequential series study with two different phases during four different time periods. Patients were divided based on TXA usage and route of administration: those with and without IV TXA (IVTA‐I and no‐IVTA groups, respectively) and those with and without intraarticular TXA (TITA and IVTA‐II groups, respectively). Both IVTA‐II and TITA groups had IV TXA, and all four groups used topical bathed TXA. These four groups had 100 cases each. The primary outcomes were evaluated with total blood loss and postoperative hemoglobin level.

RESULTS

The total blood loss was 1106 and 875 mL in the no‐IVTA and IVTA‐I groups, respectively (p < 0.05). Postoperative Hb was 10.9 and 11.51 g/dL in the no‐IVTA and IVTA‐I groups, respectively (p < 0.05). Total blood loss was 813 and 646 mL in the IVTA‐II and TITA groups, respectively (p < 0.05). Intraarticular with IV and bathed TXA administration was more effective than IV and bathed TXA in reducing blood loss.

CONCLUSION

This study suggests that the combined administration of topical intraarticular, bathed, and IV TXA was effective in reducing blood loss in THA patients.
Phylogeny and evolution of shallow‐water squat lobsters (Decapoda, Galatheoidea) from the Indo‐Pacific
Authors: Palero Ferran , Robainas‐Barcia Aymee , Corbari Laure , Macpherson Enrique
Published: December 2016

Squat lobsters have a worldwide distribution and are highly visible crustaceans living in a broad range of habitats. In this study, partial sequences of two mitochondrialDNAgenes (16SrRNAandCOI) and a nuclear gene (H3) were obtained for all but one of the known species of the shallow‐water generaSadayoshia(Munididae) andLauriea,MacrotheaandTriodonthea(Galatheidae).Lauriea siagianiappeared to be phylogenetically closer toTriodontheaandMacrotheathan to otherLaurieaspecies, suggesting the need for taxonomic re‐evaluation of these taxa. All species ofSadayoshiaformed a monophyletic group that would have diverged during the Paleogene (around 50 Mya). Our results support the hypothesis that the late Paleogene–Neogene transition was a period of rapid diversification for shallow‐water species of both Galatheidae and Munididae in the Indo‐Pacific region. This is probably related to high tectonic activity among the Eurasian, Philippine Sea, Indo‐Australian and Pacific plates and corresponding changes in distribution of habitats and ocean currents during the late Paleogene. Finally, the tropical south‐west Pacific province is identified as a major diversification centre for shallow‐water squat lobsters, from where species dispersed to other Pacific and Indian Ocean regions.
The Impact of the Environmental Documentary Movies on Pre-service German Teachers’ Environmental Attitudes
Authors: Alyaz Yunus , Isigicok Erkan , Gursoy Esim
Published: December 2016

This study examines the environmental attitudes of Turkish pre-service teachers of German as a foreign language using the German version of The Revised New Ecological Paradigm Scale (RNEP) and aims to compare New Ecological Paradigm (NEP) level of participants before and after a larger research project that uses documentary movies as a language teaching material. The comparisons were made according to demographic variables such as gender, age, education and language level when determining the NEP levels. A total of 170 pre-service German teachers (147 females, 23 males; age 17-32) contributed to the study. The findings from the present study indicate that environmental education is the most consistent factor in its relationship to levels of environmental concern, which was supported by the previous literature. The results suggest that trans-disciplinary environmental education is prior and necessary for individuals to increase their awareness and to develop abilities to reflect on their environmental responsibilities. The results of the present study also evidence that the use of environmental documentary movies have an important potential to foster environmental awareness of pre-service teachers.
Network properties of interstitial cells of Cajal affect intestinal pacemaker activity and motor patterns, according to a mathematical model of weakly coupled oscillators
Authors: Wei Ruihan , Parsons Sean P. , Huizinga Jan D.
Published: December 2016

New Findings

What is the central question of this study?

What are the effects of interstitial cells of Cajal (ICC) network perturbations on intestinal pacemaker activity and motor patterns?

What is the main finding and its importance?

Two‐dimensional modelling of the ICC pacemaker activity according to a phase model of weakly coupled oscillators showed that network properties (coupling strength between oscillators, frequency gradient and frequency noise) strongly influence pacemaker network activity and subsequent motor patterns. The model explains motor patterns observed in physiological conditions and provides predictions and testable hypotheses for effects of ICC loss and frequency modulation on the motor patterns.

Interstitial cells of Cajal (ICC) are the pacemaker cells of gut motility and are associated with motility disorders. Interstitial cells of Cajal form a network, but the contributions of its network properties to gut physiology and dysfunction are poorly understood. We modelled an ICC network as a two‐dimensional network of weakly coupled oscillators with a frequency gradient and showed changes over time in video and graphical formats. Model parameters were obtained from slow‐wave‐driven contraction patterns in the mouse intestine and pacemaker slow‐wave activities from the cat intestine. Marked changes in propagating oscillation patterns (including changes from propagation to non‐propagating) were observed by changing network parameters (coupling strength between oscillators, the frequency gradient and frequency noise), which affected synchronization, propagation velocity and occurrence of dislocations (termination of an oscillation). Complete uncoupling of a circumferential ring of oscillators caused the proximal and distal section to desynchronize, but complete synchronization was maintained with only a single oscillator connecting the sections with high enough coupling. The network of oscillators could withstand loss; even with 40% of oscillators lost randomly within the network, significant synchronization and anterograde propagation remained. A local increase in pacemaker frequency diminished anterograde propagation; the effects were strongly dependent on location, frequency gradient and coupling strength. In summary, the model puts forth the hypothesis that fundamental changes in oscillation patterns (ICC slow‐wave activity or circular muscle contractions) can occur through physiological modulation of network properties. Strong evidence is provided to accept the ICC network as a system of coupled oscillators.
A family of recurrence generated sigmoidal functions based on the Verhulst logistic function. Some approximation and modelling aspects
Authors: Kyurkchiev Nikolay
Published: December 2016

In this note we construct a family of recurrence generated sigmoidal logistic functions based on the Verhulst logistic function.We prove estimates for the Hausdorff approximation of the Heaviside step function by means of this family. Numerical examples, illustrating our results are given.
SiO2 etching in an Ar/c-C4F8/O2 dual frequency capacitively coupled plasma
Authors: Rauf Shahid , Balakrishna Ajit
Published: December 2016

SiO2 etching in an Ar/c-C4F8/O2 dual frequency (13.56 and 60 MHz) capacitively coupled plasma is examined in this paper. Experiments were done in a dilute mixture of c-C4F8/O2 in Ar for a wide range of conditions (low frequency power, c-C4F8 flow rate, O2 flow rate, total flow rate, and gas pressure), and the SiO2 etch rate was measured at multiple locations on 300 mm wafers. A two-dimensional hybrid fluid-kinetic plasma model was used to understand the experimental observations. A surface coverage based etch mechanism was found to best capture the experimental results over the range of conditions considered. In this mechanism, the SiO2 surface gets partially covered by a fluorocarbon thin film, and SiO2 is etched by energetic ions in the presence of these fluorocarbons. Conditions that enhance fluorocarbon coverage such as higher c-C4F8 flow rate or lower O2 flow rate lead to higher SiO2 etch rate. Many relevant quantities such as the fluxes of ions and neutral radicals to the wafer and ion energy sensitively depend on gas pressure. However, their effects on SiO2 etching were found to partially cancel each other, and the SiO2 etch rate exhibited only weak dependence on pressure. In order to capture experimentally observed uniformity trends, electron heating needed to be treated kinetically (using a Monte Carlo model) in the plasma model. The surface coverage based etch model is also compared to a thickness based dielectric etch mechanism, which is more applicable to fluorocarbon rich plasmas.
Influence of copper nanowires grown in a dielectric layer on the performance of dielectric barrier discharge
Authors: He Zhao , Liang Zhihu , Zhang Xiaoning , Liu Chunliang
Published: December 2016

This letter describes the fabrication of copper nanowires within a nanoporous anodic alumina oxide (AAO) layer by electrodeposition through an AAO template. The diameter of nanowires less than 100 nm is generally about 50 nm, which corresponds to the diameter of the nanopores, and can be controlled by the anodic oxidation voltage. Using the AAO with nanowires as the dielectric layer of the dielectric barrier discharge device enables a typical reduction in the breakdown and extinction voltage by about 12%–18%, and 22% at most, in the Neon pressure range of 10–90 kPa. The gas discharge intensity is also enhanced. The field emission property of the integrated nanowires is measured in a vacuum environment, and the resulting emission current density of 0.1 μA/cm2 at an electric field of 5.5 V/μm is three times larger than that of a device without nanowires. This indicates that the reduction in operating voltage is mainly due to additional electrons produced by the nanowires. Additionally, the resulting Fowler–Nordheim characteristic clearly demonstrates the field emission behavior of the copper nanowires.
Genome Sequence of Actinomyces naeslundii Strain ATCC 27039, Isolated from an Abdominal Wound Abscess
Authors: Mashimo Chiho , Yamane Kazuyoshi , Yamanaka Takeshi , Maruyama Hugo , Wang Pao-Li , Komasa Satoshi , Okazaki Joji , Nambu Takayuki
Published: December 2016

Here, we present the complete genome sequence of
Actinomyces naeslundii
strain ATCC 27039, isolated from an abdominal wound abscess. This strain is genetically transformable and will thus provide valuable information related to its crucial role in oral multispecies biofilm development.
Draft Whole-Genome Sequence of the Alkaliphilic Alishewanella aestuarii Strain HH-ZS, Isolated from Historical Lime Kiln Waste-Contaminated Soil
Authors: Salah Zohier B. , Rout Simon P. , Humphreys Paul N.
Published: December 2016

Here, we present the whole-genome sequence of an environmental Gram-negative
Alishewanella aestuarii
strain (HH-ZS), isolated from the hyperalkaline contaminated soil of a historical lime kiln in Buxton, United Kingdom.
Irreducible posterolateral elbow dislocation: a rare injury
Authors: Fenelon Christopher , Zafar Muhammed M , Sheridan Gerard Anthony , Kearns Stephen
Published: December 2016

Posterolateral dislocation of the elbow is an injury commonly treated in the emergency department by closed reduction. Very rarely it can be irreducible and require open reduction. Only four cases of irreducible posterolateral elbow dislocation have been described in the literature over the past 50 years. We report the case of a 20-year-old man who sustained such an injury. Open reduction was performed and revealed the radial head protruding or ‘buttonholing’ through the lateral collateral ligament complex. This case highlights that continued closed reduction of the elbow should not be attempted, as a mechanical block to reduction can occur making reduction impossible.
On the SLq(2) extension of the standard model and the concept of charge
Authors: Finkelstein Robert J.
Published: December 2016

Our SLq(2) extension of the standard model is constructed by replacing the elementary field operators, [Formula: see text], of the standard model by [Formula: see text] where [Formula: see text] is an element of the [Formula: see text]-dimensional representation of the SLq(2) algebra, which is also the knot algebra. The allowed quantum states [Formula: see text] are restricted by the topological conditions [Formula: see text] postulated between the states of the quantum knot [Formula: see text] and the corresponding classical knot [Formula: see text] where the [Formula: see text] are (the number of crossings, the writhe, the rotation) of the 2d projection of the corresponding oriented classical knot. Here, [Formula: see text] is an odd number that is required by the difference in parity between [Formula: see text] and [Formula: see text]. There is also the empirical restriction on the allowed states [Formula: see text] that holds at the [Formula: see text] level, connecting quantum trefoils [Formula: see text] with leptons and quarks [Formula: see text]. The so-constructed knotted leptons and quarks turn out to be composed of three [Formula: see text] particles which unexpectedly agree with the preon models of Harrari and Shupe. The [Formula: see text] particles, being electroweak neutral, are dark and plausibly greatly outnumber the quarks and leptons. The SLq(2) or [Formula: see text] measure of charge has a direct physical interpretation since [Formula: see text] is the total number of preonic charges while [Formula: see text] and [Formula: see text] are the numbers of writhe and rotation sources of preonic charge. The total SLq(2) charge of a particle, measured by writhe and rotation and composed of preons, sums the signs of the counterclockwise turns [Formula: see text] and clockwise turns [Formula: see text] that any energy–momentum current makes in going once around the knot. In this way, the handedness of the knot reduces charge to a geometric concept similar to the way that curvature of space–time encodes mass and energy. According to this model, the leptons and quarks are [Formula: see text] particles, the preons are [Formula: see text] particles, and the [Formula: see text] particles are candidates for dark matter. It is possible to understand [Formula: see text] as a simple deformation parameter or as the ratio [Formula: see text] of the electroweak to the gluon coupling constants.
Solar-system tests of the relativistic gravity
Authors: Ni Wei-Tou
Published: December 2016

In 1859, Le Verrier discovered the Mercury perihelion advance anomaly. This anomaly turned out to be the first relativistic gravity effect observed. During the 157 years to 2016, the precisions and accuracies of laboratory and space experiments, and of astrophysical and cosmological observations on relativistic gravity have been improved by 3–4 orders of magnitude. The improvements have been mainly from optical observations at first followed by radio observations. The achievements for the past 50 years are from radio Doppler tracking and radio ranging together with Lunar Laser Ranging (LLR). At present, the radio observations and LLR experiments are similar in the accuracy of testing relativistic gravity. We review and summarize the present status of solar system tests of relativistic gravity. With planetary laser ranging, spacecraft laser ranging and interferometric laser ranging (laser Doppler ranging) together with the development of drag-free technology, the optical observations will improve the accuracies by another 3–4 orders of magnitude in both the equivalence principle tests and solar system dynamics tests of relativistic gravity. Clock tests and atomic interferometry tests of relativistic gravity will reach an ever-increasing precision. These will give crucial clues in both experimental and theoretical aspects of gravity, and may lead to answers to some profound issues in gravity and cosmology.
Synthesis of asymmetric guanidiniumphenyl-aminophenyl porphyrins
Authors: Perrier Arnaud , Mothes Emmanuelle , Bonduelle Colin , Pratviel Geneviève
Published: December 2016

The symmetric meso-tetrakis(4-aminophenyl)porphyrin was reacted with nonstoichiometric amount of [Formula: see text],[Formula: see text]-bis(tert-butoxycarbonyl)-[Formula: see text]-methylisothiourea with respect to the amine functions of the porphyrin to afford (after deprotection of the Boc residues) the asymmetric guanidiniumphenyl-aminophenyl porphyrins carrying two or three guanidiniumphenyl substituents at the meso-position. The adjacent and opposite isomers of the bis(guanidiniumphenyl) modified porphyrins were isolated separately.
Ischemic preconditioning in pigs: a causal role for signal transducer and activator of transcription 3
Authors: Gent Sabine , Skyschally Andreas , Kleinbongard Petra , Heusch Gerd
Published: December 2016

Ischemic preconditioning (IPC), i.e., brief episodes of nonlethal myocardial ischemia-reperfusion (I/R) before sustained ischemia with subsequent reperfusion, reduces infarct size in all species tested so far, including humans. In rodents, the cardioprotective signal transduction causally involves an activation of Akt, ERK1/2, and STAT3. However, there are apparent species differences in the signal transduction between rodents and larger mammals such as pigs, where data on IPC's signal transduction are inconsistent for Akt and ERK1/2. The role of STAT3 has not yet been analyzed. Pigs were subjected to 60 min of left anterior descending coronary artery occlusion and 180 min of reperfusion without or with IPC (2 cycles of 3-min occlusion separated by 2 min of reperfusion 15 min before sustained I/R). Infarct size was analyzed by triphenyl tetrazolium chloride staining, and Akt, ERK1/2, and STAT3 phosphorylation was quantified in myocardial biopsies taken at baseline and early reperfusion. AG490 was used to block the STAT3 signaling pathway. IPC reduced infarct size (%area at risk; mean ± SE, I/R, 45 ± 3 vs. IPC, 18 ± 3, P < 0.05). Akt and ERK1/2 phosphorylation was increased at early reperfusion without and with IPC. In contrast, STAT3 phosphorylation at early reperfusion was only increased with IPC (%baseline; mean ± SE, I/R, 126 ± 29 vs. IPC, 408 ± 147, P < 0.05). AG490 prevented the IPC-related increase of STAT3 phosphorylation at reperfusion (%baseline; mean ± SE, 82 ± 12) and abolished IPC's cardioprotection (%area at risk; mean ± SE, 35 ± 4). In pigs, increased phosphorylation of STAT3 is causally involved, whereas Akt and ERK1/2 seem to play no role in IPC's cardioprotection.

NEW & NOTEWORTHY In pig hearts in situ, ischemic preconditioning (IPC) causally involves increased phosphorylation of STAT3, whereas Akt and ERK1/2 play no role for cardioprotection. The cardioprotective signal transduction of IPC is similar to that of ischemic postconditioning and remote IPC in pigs.
Short-term intense exercise training reduces stress markers and alters the transcriptional response to exercise in skeletal muscle
Authors: Hinkley J. Matthew , Konopka Adam R. , Suer Miranda K. , Harber Matthew P.
Published: December 2016

The purpose of this investigation was to examine the influence of short-term intense endurance training on cycling performance, along with the acute and chronic signaling responses of skeletal muscle stress and stability markers. Ten recreationally active subjects (25 ± 2 yr, 79 ± 3 kg, 47 ± 2 ml·kg−1·min−1) were studied before and after a 12-day cycling protocol to examine the effects of short-term intense (70–100% V̇o2max) exercise training on resting and exercise-induced regulation of molecular factors related to skeletal muscle cellular stress and protein stability. Skeletal muscle biopsies were taken at rest and 3 h following a 20-km cycle time trial on days 1 and 12 to measure mRNA expression and protein content. Training improved ( P < 0.05) cycling performance by 5 ± 1%. Protein oxidation was unaltered on day 12, while resting SAPK/JNK phosphorylation was reduced ( P < 0.05), suggesting a reduction in cellular stress. The maintenance in the myocellular environment may be due to synthesis of cytoprotective markers, along with enhanced degradation of damage proteins, as training tended ( P < 0.10) to increase resting protein content of manganese superoxide dismutase and heat shock protein 70 (HSP70), while mRNA expression of MuRF-1 was elevated ( P < 0.05). Following training ( day 12), the acute exercise-induced transcriptional response of TNF-α, NF-κB, MuRF-1, and PGC1α was attenuated ( P < 0.05) compared with day 1. Collectively, these data suggest that short-term intense training enhances protein stability, creating a cellular environment capable of resistance to exercise-induced stress, which may be favorable for adaptation.
Data integration in physiology using Bayes’ rule and minimum Bayes’ factors: deubiquitylating enzymes in the renal collecting duct
Authors: Xue Zhe , Chen Jia-Xu , Zhao Yue , Medvar Barbara , Knepper Mark A.
Published: December 2016

A major challenge in physiology is to exploit the many large-scale data sets available from “-omic” studies to seek answers to key physiological questions. In previous studies, Bayes’ theorem has been used for this purpose. This approach requires a means to map continuously distributed experimental data to probabilities (likelihood values) to derive posterior probabilities from the combination of prior probabilities and new data. Here, we introduce the use of minimum Bayes’ factors for this purpose and illustrate the approach by addressing a physiological question, “Which deubiquitylating enzymes (DUBs) encoded by mammalian genomes are most likely to regulate plasma membrane transport processes in renal cortical collecting duct principal cells?” To do this, we have created a comprehensive online database of 110 DUBs present in the mammalian genome ( https://hpcwebapps.cit.nih.gov/ESBL/Database/DUBs/ ). We used Bayes’ theorem to integrate available information from large-scale data sets derived from proteomic and transcriptomic studies of renal collecting duct cells to rank the 110 known DUBs with regard to likelihood of interacting with and regulating transport processes. The top-ranked DUBs were OTUB1, USP14, PSMD7, PSMD14, USP7, USP9X, OTUD4, USP10, and UCHL5. Among these USP7, USP9X, OTUD4, and USP10 are known to be involved in endosomal trafficking and have potential roles in endosomal recycling of plasma membrane proteins in the mammalian cortical collecting duct.
Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion–Positive Cholangiocarcinoma
Authors: Goyal Lipika , Saha Supriya K. , Liu Leah Y. , Siravegna Giulia , Leshchiner Ignaty , Ahronian Leanne G. , Lennerz Jochen K. , Vu Phuong , Deshpande Vikram , Kambadakone Avinash , Mussolin Benedetta , Reyes Stephanie , Henderson Laura , Sun Jiaoyuan Elisabeth , Van Seventer Emily E. , Gurski Joseph M. , Baltschukat Sabrina , Schacher-Engstler Barbara , Barys Louise , Stamm Christelle , Furet Pascal , Ryan David P. , Stone James R. , Iafrate A. John , Getz Gad , Porta Diana Graus , Tiedt Ralph , Bardelli Alberto , Juric Dejan , Corcoran Ryan B. , Bardeesy Nabeel , Zhu Andrew X.
Published: December 2016

Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion–positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases. Serial analysis of cfDNA demonstrated multiple recurrent point mutations in the FGFR2 kinase domain at progression. Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intralesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation led to BGJ398 resistance and was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism that may guide the development of future therapeutic strategies.

Significance: We report the first genetic mechanisms of clinical acquired resistance to FGFR inhibition in patients with FGFR2 fusion–positive ICC. Our findings can inform future strategies for detecting resistance mechanisms and inducing more durable remissions in ICC and in the wide variety of cancers where the FGFR pathway is being explored as a therapeutic target. Cancer Discov; 7(3); 252–63. ©2016 AACR.

See related commentary by Smyth et al., p. 248.

This article is highlighted in the In This Issue feature, p. 235
Prothrombotic Fibrin Clot Phenotype Is Associated With Recurrent Pulmonary Embolism After Discontinuation of Anticoagulant Therapy
Authors: Zabczyk Michal , Plens Krzysztof , Wojtowicz Wioletta , Undas Anetta
Published: December 2016

Objective—

Pulmonary embolism (PE) is a life-threatening manifestation of venous thromboembolism with a high recurrence rate after anticoagulation cessation. Recently, we have reported that prothrombotic clot phenotype in venous thromboembolism patients is associated with an increased risk of recurrent deep-vein thrombosis.

Approach and Results—

We tested whether abnormal clot properties are predictive of recurrent PE. We investigated 156 consecutive white patients aged 18 to 65 years after the first-ever provoked or unprovoked PE (n=89), with or without deep-vein thrombosis. Plasma fibrin clot permeability (K
s
), turbidity measurements, calibrated automated thrombography, and efficiency of fibrinolysis using clot lysis time, maximum D-dimer levels, and rate of increase in D-dimer levels were evaluated at ≥3 months of anticoagulant therapy, at least 4 weeks since the anticoagulation withdrawal. The primary end point was recurrent PE during a median follow-up of 50 months. Recurrent PE was diagnosed in 23 (14.7%; 5%/yr) patients. Recurrent PE was associated with formation of denser fibrin networks reflected by lower K
s
(
P
=0.007) and impaired fibrinolysis, as evidenced by prolonged clot lysis time (
P
=0.012) and reduced maximum rate of increase in D-dimer levels in the lysis assay (
P
=0.004). Patients with recurrent PE had higher plasma D-dimer (
P
<0.001) and thrombin peak (
P
=0.007) compared with the remainder, whereas turbidity measurements and maximum D-dimer levels did not differ in the recurrence. Multivariate model showed that independent predictors of recurrent PE were female sex, unprovoked venous thromboembolism, higher plasma D-dimer, reduced K
s
, and reduced maximum rate of increase in D-dimer levels in the lysis assay (all
P
<0.05).

Conclusions—

Altered fibrin clot properties including formation of more compact clots displaying impaired susceptibility to lysis may predispose to recurrent PE.
Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability
Authors: Xu Rende , Li Chenguang , Wu Yizhe , Shen Li , Ma Jianying , Qian Juying , Ge Junbo
Published: December 2016

Objective—

Emerging evidence indicates that proinflammatory macrophage polarization imbalance plays a key role in atherosclerotic plaque progression and instability. The calcium-activated potassium channel KCa3.1 is critically involved in macrophage activation and function. However, the role of KCa3.1 in macrophage polarization is unknown. This study investigates the potential role of KCa3.1 in transcriptional regulation in macrophage polarization and its relationship to plaque instability.

Approach and Results—

Human monocytes were differentiated into macrophages using macrophage colony-stimulating factor. Macrophages were then polarized into proinflammatory M1 cells by interferon-γ and lipopolysaccharide and into alternative M2 macrophages by interleukin-4. A model for plaque instability was induced by combined partial ligation of the left renal artery and left common carotid artery in apolipoprotein E knockout mice. Significant upregulation of KCa3.1 expression was observed during the differentiation of human monocytes into macrophages. Blocking KCa3.1 significantly reduced the expression of proinflammatory genes during macrophages polarization. Further mechanistic studies indicated that blocking KCa3.1 inhibited macrophage differentiation toward the M1 phenotype by downregulating signal transducer and activator of transcription-1 phosphorylation. In animal models, KCa3.1 blockade therapy strikingly reduced the incidence of plaque rupture and luminal thrombus in carotid arteries, decreased the expression of markers associated with M1 macrophage polarization, and enhanced the expression of M2 markers within atherosclerotic lesions.

Conclusions—

These results suggest that blocking KCa3.1 suppresses plaque instability in advanced stages of atherosclerosis by inhibiting macrophage polarization toward an M1 phenotype.
Novel Thrombotic Function of a Human SNP in
STXBP5
Revealed by CRISPR/Cas9 Gene Editing in Mice
Authors: Zhu Qiuyu Martin , Ko Kyung Ae , Ture Sara , Mastrangelo Michael A. , Chen Ming-Huei , Johnson Andrew D. , O’Donnell Christopher J. , Morrell Craig N. , Miano Joseph M. , Lowenstein Charles J.
Published: December 2016

Objective—

To identify and characterize the effect of a SNP (single-nucleotide polymorphism) in the
STXBP5
locus that is associated with altered thrombosis in humans. GWAS (genome-wide association studies) have identified numerous SNPs associated with human thrombotic phenotypes, but determining the functional significance of an individual candidate SNP can be challenging, particularly when in vivo modeling is required. Recent GWAS led to the discovery of STXBP5 as a regulator of platelet secretion in humans. Further clinical studies have identified genetic variants of
STXBP5
that are linked to altered plasma von Willebrand factor levels and thrombosis in humans, but the functional significance of these variants in
STXBP5
is not understood.

Approach and Results—

We used CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated 9) techniques to produce a precise mouse model carrying a human coding SNP
rs1039084
(encoding human
p. N436S
) in the
STXBP5
locus associated with decreased thrombosis. Mice carrying the orthologous human mutation (encoding
p. N437S
in mouse STXBP5) have lower plasma von Willebrand factor levels, decreased thrombosis, and decreased platelet secretion compared with wild-type mice. This thrombosis phenotype recapitulates the phenotype of humans carrying the minor allele of
rs1039084
. Decreased plasma von Willebrand factor and platelet activation may partially explain the decreased thrombotic phenotype in mutant mice.

Conclusions—

Using precise mammalian genome editing, we have identified a human nonsynonymous SNP
rs1039084
in the
STXBP5
locus as a causal variant for a decreased thrombotic phenotype. CRISPR/Cas9 genetic editing facilitates the rapid and efficient generation of animals to study the function of human genetic variation in vascular diseases.
Protective Aptitude of Annexin A1 in Arterial Neointima Formation in Atherosclerosis-Prone Mice—Brief Report
Authors: de Jong Renske J. , Paulin Nicole , Lemnitzer Patricia , Viola Joana R. , Winter Carla , Ferraro Bartolo , Grommes Jochen , Weber Christian , Reutelingsperger Chris , Drechsler Maik , Soehnlein Oliver
Published: December 2016

Objective—

Restenosis as a consequence of arterial injury is aggravated by inflammatory pathways. Here, we investigate the role of the proresolving protein annexin A1 (AnxA1) in healing after wire injury.

Approach and Results—

Apoe
−/−
and
Apoe
−/−
Anxa1
−/−
mice were subjected to wire injury while fed a high-cholesterol diet. Subsequently, localization of AnxA1 and AnxA1 plasma levels were examined. AnxA1 was found to localize within endothelial cells and macrophages in the neointima. Levels of AnxA1 in the plasma and its lesional expression negatively correlated with neointima size, and in the absence of AnxA1, neointima formation was aggravated by the accumulation and proliferation of macrophages. In contrast, reendothelialization and smooth muscle cell infiltration were not affected in
Apoe
−/−
Anxa1
−/−
mice.

Conclusions—

AnxA1 is protective in healing after wire injury and could, therefore, be an attractive therapeutic compound to prevent from restenosis after vascular damage.
Risk Factors for Coarctation of the Aorta on Prenatal Ultrasound
Authors: Familiari Alessandra , Morlando Maddalena , Khalil Asma , Sonesson Sven-Erik , Scala Carolina , Rizzo Giuseppe , Del Sordo Gelsomina , Vassallo Chiara , Elena Flacco Maria , Manzoli Lamberto , Lanzone Antonio , Scambia Giovanni , Acharya Ganesh , D’Antonio Francesco
Published: December 2016

Background:

Prenatal diagnosis of coarctation of the aorta (CoA) is still challenging and affected by high rates of false-positive diagnoses. The aim of this study was to ascertain the strength of association and to quantify the diagnostic accuracy of different ultrasound signs in predicting CoA prenatally.

Methods:

Medline, Embase, CINAHL, and Cochrane databases were searched. Random-effects and hierarchical summary receiver operating characteristic model meta-analyses were used to analyze the data.

Results:

Seven hundred ninety-four articles were identified, and 12 (922 fetuses at risk for CoA) articles were included. Mean mitral valve diameter
z
score was lower (
P
<0.001) and the mean tricuspid valve diameter
z
score was higher in fetuses with CoA than in those without CoA (
P
=0.01). Mean aortic valve diameter
z
score was lower in fetuses with CoA than in healthy fetuses (
P
≤0.001), but the ascending aorta diameter, expressed as
z
score or millimeters, was similar between groups (
P
=0.07 and 0.47, respectively). Mean aortic isthmus diameter
z
scores measured either in sagittal (
P
=0.02) or in 3-vessel trachea view (
P
<0.001) were lower in fetuses with CoA. Conversely, the mean pulmonary artery diameter
z
score, the right/left ventricular and pulmonary artery/ascending aorta diameter ratios were higher (
P
<0.001,
P
=0.02, and
P
=0.02, respectively) in fetuses with CoA in comparison with controls, although aortic isthmus/arterial duct diameter ratio was lower in fetuses with CoA than in those without CoA (
P
<0.001). The presence of coarctation shelf and aortic arch hypoplasia were more common in fetuses with CoA than in controls (odds ratio, 26.0; 95% confidence interval, 4.42–153;
P
<0.001 and odds ratio, 38.2; 95% confidence interval, 3.01–486;
P
=0.005), whereas persistent left superior vena cava (
P
=0.85), ventricular septal defect (
P
=0.12), and bicuspid aortic valve (
P
=0.14) did not carry an increased risk for this anomaly. Multiparametric diagnostic models integrating different ultrasound signs for the detection of CoA were associated with an increased detection rate.

Conclusions:

The detection rate of CoA may improve when a multiple-criteria prediction model is adopted. Further large multicenter studies sharing the same imaging protocols are needed to develop objective models for risk assessment in these fetuses.