bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of lactic acidaemia in patients with advanced heart failure and depressed cardiac output
Authors: Adamo Luigi , Nassif Michael E. , Novak Erik , LaRue Shane J. , Mann Douglas L.
Published: September 2016

Aims

Heart failure (HF) has been defined classically as a condition in which the heart is unable to deliver sufficient oxygen to match the needs of the metabolizing tissues. Surprisingly, this definition has never been validated. The goal of this study was to determine the prevalence of elevated lactate levels in a cohort of patients with advanced heart failure.

Methods and results

We retrospectively analysed the arterio‐venous oxygen difference (A–V O2), haemodynamics, and plasma lactate levels in stage D heart failure patients who were being evaluated for a left ventricular assist device (LVAD). We identified 359 patients with a right heart catheterization (RHC) performed prior to LVAD implantation. Plasma lactate was available for 96 patients. RHC showed that 93% of the patients had an A–V O2 above the upper limit of normal (>5 mL/100 mL). Among patients with measured lactate levels, the prevalence of elevated lactate (>2.1 mmol/L) was 25% (95% confidence interval 16.7–34.9). The A–V O2 was widened in all patients with elevated lactate, but plasma lactate did not correlate with A–V O2 (r = 0.02) and only 27% of patients with increased A–V O2 had elevated plasma lactate.

Conclusions

Lactate levels were normal in ∼75% of the patients with advanced heart failure and a widened A–V O2, suggesting that the cardiac output was sufficient to meet the metabolic needs of the peripheral metabolizing tissues. Given that ∼4% of heart failure patients are in NYHA class IV, these findings suggest that the classic definition of heart failure pertains to ∼1% of patients with HF.
Carotid body resection for sympathetic modulation in systolic heart failure: results from first‐in‐man study
Authors: Niewinski Piotr , Janczak Dariusz , Rucinski Artur , Tubek Stanislaw , Engelman Zoar J. , Piesiak Pawel , Jazwiec Przemyslaw , Banasiak Waldemar , Fudim Marat , Sobotka Paul A. , Javaheri Shahrokh , Hart Emma C.J. , Paton Julian F.R. , Ponikowski Piotr
Published: September 2016

Aims

Augmented reflex responses from peripheral chemoreceptors, which are mainly localized in the carotid bodies (CBs), characterize patients with systolic heart failure and contribute to adrenergic hyperactivation. We investigated whether surgical resection of CBs in these patients can be performed safely to decrease sympathetic tone.

Methods and results

We studied 10 male patients with systolic heart failure (age, 59 ± 3 years; LVEF, 27 ± 7%) who underwent unilateral right‐sided CB resection (four patients) or bilateral CB resection (six patients). Primary endpoints of the study were changes in muscle sympathetic nerve activity (MSNA) and peripheral chemosensitivity measured as ventilatory response to hypoxia from baseline to 1 month post‐CB resection. Safety analysis included analysis of arterial blood gas and oxygenation at night through 2 months post‐procedure and adverse events assessed up to 12 months. At the 1‐month visit, CB resection was associated with a significant decrease both in MSNA (86.6 ± 3.1 vs. 79.7 ± 4.2 bursts/100 beats, P = 0.03) and in peripheral chemosensitivity (1.35 ± 0.19 vs. 0.41 ± 0.17 L/min/SpO2, P = 0.005). It also resulted in improved exercise tolerance. Amongst some patients with bilateral CB resection, there was a trend towards worsening of oxygen saturation at night, which in one case required therapy with non‐invasive ventilation.

Conclusion

We present first‐in‐man evidence that CB resection in patients with systolic heart failure is associated with a decrease in sympathetic activity. A bilateral procedure may carry a risk of worsening oxygenation at night. CB modulation constitutes an interesting research avenue, but careful consideration of the balance between safety and efficacy is necessary before further clinical trials.
Three‐Dimensional Co‐ and Mn‐MOFs Containing a C2h‐Symmetric Terphenyl‐3,3′‐dicarboxylate Linker and Their Magnetic Properties
Authors: Kim Hyun‐Chul , Gu Ja‐Min , Kim Youngmee , Lee Do Nam , Huh Seong
Published: September 2016

We report herein two new isostructural, three‐dimensional (3D) MOFs with the general formula [M(3,3′‐tpdc)(dmf)] [M = CoII (I), MnII (II)] resulting from the assembly of a metal ion and the C2h‐symmetric ditopic bridging ligand terphenyl‐3,3′‐dicarboxylate (3,3′‐tpdc). Both isostructural MOFs crystallize in the monoclinic space group C2/c. The metal ion is coordinated by four Ocarboxylate (η1:η1:µ2) and two µ2‐Odmf atoms in a distorted octahedral geometry. The metal centers are interconnected through bridging 3,3′‐tpdc and dmf ligands to form a 1D chain. The resulting 1D metal chains are further interconnected by 3,3′‐tpdc ligands to form 3D frameworks without porosity. The thermolabile dmf bridging ligands were easily removed by heating at 180 °C under vacuum for 5 h. The activated MOFs I and II exhibited very low gas uptake of N2, CO2, and H2 after removal of the dmf bridging ligands. The encapsulation of iodine guest molecules by the activated I and II was also investigated. The crystal structure of iodine‐encapsulated II was also elucidated. The coordination environment of the MnII atom in II changed as a result of the loss of dmf bridging ligands. The as‐prepared MOFs I and II exhibit weak antiferromagnetic interactions in their 1D metal chains; these magnetic interactions should mainly occur between the metal ions bridged by the short carboxylate‐based ligand and dmf oxygen atoms. Thermal removal of the bridging dmf molecules led to a change in the Mn···Mn distances in the 1D chains of II that also affected its magnetic properties.
Exploring Structure–Activity Relationships in Synthetic Antimicrobial Peptides (synAMPs) by a Ferrocene Scan
Authors: Slootweg Jack C. , Prochnow Pascal , Bobersky Sandra , Bandow Julia E. , Metzler‐Nolte Nils
Published: September 2016

Synthetic antimicrobial peptides (SynAMPs) are an interesting class of novel antibiotic agents used to fight infections caused by resistant bacterial strains. Herein we report the synthesis of a ferrocene‐containing lysine (FcLys) suitable for standard Fmoc/tBu solid‐phase peptide synthesis. A library of (Arg‐Trp)3‐based antimicrobial peptides have been synthesized in which all the tryptophan residues were replaced systematically by FcLys and their biological activities evaluated. We call this technique a “ferrocene scan”, in analogy with the well‐established “alanine scan” used to investigate crucial interactions in peptides. The FcLys‐peptides showed excellent activity against gram‐positive bacterial strains compared with the metal‐free parent peptide, including a four‐fold increase in activity against the resistant bacterial strain MRSA. Moreover, some members of this family of ferrocenoyl peptides also showed an up to 16‐fold increased activity compared with the parent peptide against the gram‐negative bacterium A. baumannii. This behavior distinguishes these synAMPs from the previously investigated N‐terminally ferrocenoylated peptides, which in general showed a dramatically reduced activity against gram‐negative bacteria. The FcLys‐peptides also showed low hemolytic activity against red blood cells (RBCs), which indicates excellent bacterial selectivity, making them an attractive class of novel peptide‐based organometallic antimicrobial agents.
Enzymatic synthesis of steryl hydroxycinnamates and their antioxidant activity
Authors: Schär Aline , Liphardt Silvia , Nyström Laura
Published: September 2016

Steryl hydroxycinnamates are of increasing interest as they are antioxidant esters of phytosterols with potential cholesterol lowering properties. Apart from ferulates, also other plant steryl hydroxycinnamates have been identified in natural products. In this study hydroxycinnamic acid derivatives were ethylated enzymatically using Rhizomucor miehei lipase (yields from 16 to 97%), and transesterified by lipase from Candida rugosa to yield steryl hydroxycinnamates (yields from <LOQ to 55%). The influence of the structural differences between the hydroxycinnamic acid derivatives on the esterification yields was very different for the two lipases applied. Furthermore, the antioxidant activity of steryl and stearyl hydroxycinnamates was evaluated by DPPH radical scavenging activity and in two methyl linoleate systems. In bulk methyl linoleate, free sinapic acid showed the highest antioxidant activity over other sinapates, whereas in emulsified methyl linoleate, stearyl sinapate was highest. In conclusion, the enzymatic synthesis and antioxidant activity of steryl hydroxycinnamates is highly dependent on the acid structure.

Practical applications: The enzymatic esterification of hydroxycinnamic acids is an environmentally friendly procedure to generate nonpolar hydroxycinnamates. These compounds have a broadened field of application due to their adapted polarity, and therefore potentially have an improved antioxidant activity in a wider range of food applications including multiphase systems. In the case of steryl hydroxycinnamates, the nonpolar part of the molecule brings additional health benefits, such as the cholesterol lowering properties, which makes them even more interesting as possible food additives with multiple technological and nutritional advantages.

Hydroxycinnamic acids were ethylated enzymatically using R. miehei lipase, and transesterified by lipase from C. rugosa to yield steryl hydroxycinnamates. The influence of the structural differences between the hydroxycinnamic acids on the esterification yields was very different for the two lipases applied. Furthermore, the antioxidant activity of steryl and octadecyl hydroxycinnamates was evaluated by DPPH radical scavenging activity and in bulk and emulsified methyl linoleate system.
A combined level set/ghost cell immersed boundary representation for floating body simulations
Authors: Bihs H. , Kamath A.
Published: September 2016

A six degrees of freedom (6DOF) algorithm is implemented in the open‐source CFD code REEF3D. The model solves the incompressible Navier–Stokes equations. Complex free surface dynamics are modeled with the level set method based on a two‐phase flow approach. The convection terms of the velocities and the level set method are treated with a high‐order weighted essentially non‐oscillatory discretization scheme. Together with the level set method for the free surface capturing, this algorithm can model the movement of rigid floating bodies and their interaction with the fluid. The 6DOF algorithm is implemented on a fixed grid. The solid‐fluid interface is represented with a combination of the level set method and ghost cell immersed boundary method. As a result, re‐meshing or overset grids are not necessary. The capability, accuracy, and numerical stability of the new algorithm is shown through benchmark applications for the fluid‐body interaction problem. Copyright © 2016 John Wiley & Sons, Ltd.
A robust flux splitting method with low dissipation for all‐speed flows
Authors: Sun Di , Yan Chao , Qu Feng , Du Ruofan
Published: September 2016

In this paper, we propose a simple robust flux splitting method for all‐speed flows with low dissipation. Following the Toro‐Vazquez splitting, the inviscid flux is split into the convective and the pressure parts first. Then, we apply the Harten‐Lax‐van Leer (HLL) algorithm to each parts with low dissipation modification. Here, the modification improves the method with accurately resolving contact discontinuity and high resolution for low speed flows. Several carefully chosen numerical tests are investigated, and the results show that the proposed scheme is capable of resolving contact discontinuity, robust against the shock anomaly and accurate at all‐speeds. Because of these properties, it is expected to be widely applied to all‐speed flow studies. Copyright © 2016 John Wiley & Sons, Ltd.
An Inhomogeneous Hidden Markov Model for Efficient Virtual Machine Placement in Cloud Computing Environments
Authors: Hammer Hugo Lewi , Yazidi Anis , Begnum Kyrre
Published: September 2016

In a cloud environment virtual machines are created with different purposes, such as providing users with computers or handling web traffic. A virtual machine is created in such a way that a user will not notice any difference from working on a physical computer. A challenging problem in cloud computing is how to distribute the virtual machines on a set of physical servers. An optimal solution will provide each virtual machine with enough resources and at the same time not using more physical services (energy/electricity) than necessary to achieve this.

In this paper we investigate how forecasting of future resource requirements (CPU consumption) for each virtual machine can be used to improve the virtual machine placement on the physical servers. We demonstrate that a time‐dependent hidden Markov model with an autoregressive observation process replicates the properties of the CPU consumption data in a realistic way and forecasts future CPU consumption efficiently. Copyright © 2016 John Wiley & Sons, Ltd.
Effects of electromagnetic fields emitted by GSM phones on working memory: a meta‐analysis
Authors: Zubko O. , Gould R. L. , Gay H. C. , Cox H. J. , Coulson M. C. , Howard R. J.
Published: September 2016

Background and Objective

Current treatments for Alzheimer's Disease (AD) do not affect the course of the illness and brain stimulation techniques are increasingly promoted as potential therapeutic interventions for AD. This study reviews the effects of electromagnetic field (EMF) exposure versus sham exposure on working memory (WM) performance of healthy human participants.

Method

Online literature databases and previous systematic reviews were searched for studies of EMF and WM in participants without reported memory problems. Two thousand eight hundred and fifty seven studies were identified, and 10 studies met the inclusion criteria. An assessment of study quality was completed, and separate, random effects meta‐analyses were conducted for each of the three WM tasks included: n‐back, substitution and digit span forward.

Results

No differences were found between participants exposed to active EMF versus sham conditions in any of the three working memory tasks examined.

Conclusion

Results indicate that EMF does not affect WM during the n‐back, substitution and digit‐span tasks. Future studies should focus on the possible effects of chronic exposure to EMF in older adults with AD using a battery of comparable WM and attention tasks, before EMF can be seriously considered as a potential modulator of WM in AD. Copyright © 2016 John Wiley & Sons, Ltd.
Active delineation of Meyer's loop using oriented priors through MAGNEtic tractography (MAGNET)
Authors: Chamberland Maxime , Scherrer Benoit , Prabhu Sanjay P. , Madsen Joseph , Fortin David , Whittingstall Kevin , Descoteaux Maxime , Warfield Simon K.
Published: September 2016

Streamline tractography algorithms infer connectivity from diffusion MRI (dMRI) by following diffusion directions which are similarly aligned between neighboring voxels. However, not all white matter (WM) fascicles are organized in this manner. For example, Meyer's loop is a highly curved portion of the optic radiation (OR) that exhibits a narrow turn, kissing and crossing pathways, and changes in fascicle dispersion. From a neurosurgical perspective, damage to Meyer's loop carries a potential risk of inducing vision deficits to the patient, especially during temporal lobe resection surgery. To prevent such impairment, achieving an accurate delineation of Meyer's loop with tractography is thus of utmost importance. However, current algorithms tend to under‐estimate the full extent of Meyer's loop, mainly attributed to the aforementioned rule for connectivity which requires a direction to be chosen across a field of orientations. In this article, it was demonstrated that MAGNEtic Tractography (MAGNET) can benefit Meyer's loop delineation by incorporating anatomical knowledge of the expected fiber orientation to overcome local ambiguities. A new ROI‐mechanism was proposed which supplies additional information to streamline reconstruction algorithms by the means of oriented priors. Their results showed that MAGNET can accurately generate Meyer's loop in all of our 15 child subjects (8 males; mean age 10.2 years ± 3.1). It effectively improved streamline coverage when compared with deterministic tractography, and significantly reduced the distance between the anterior‐most portion of Meyer's loop and the temporal pole by 16.7 mm on average, a crucial landmark used for preoperative planning of temporal lobe surgery. Hum Brain Mapp 38:509–527, 2017. © 2016 Wiley Periodicals, Inc.
The neurobiology of emotion regulation in posttraumatic stress disorder: Amygdala downregulation via real‐time fMRI neurofeedback
Authors: Nicholson Andrew A. , Rabellino Daniela , Densmore Maria , Frewen Paul A. , Paret Christian , Kluetsch Rosemarie , Schmahl Christian , Théberge Jean , Neufeld Richard W.J. , McKinnon Margaret C. , Reiss Jeffrey P. , Jetly Rakesh , Lanius Ruth A.
Published: September 2016

Amygdala dysregulation has been shown to be central to the pathophysiology of posttraumatic stress disorder (PTSD) representing a critical treatment target. Here, amygdala downregulation was targeted using real‐time fMRI neurofeedback (rt‐fMRI‐nf) in patients with PTSD, allowing us to examine further the regulation of emotional states during symptom provocation. Patients (n = 10) completed three sessions of rt‐fMRI‐nf with the instruction to downregulate activation in the amygdala, while viewing personalized trauma words. Amygdala downregulation was assessed by contrasting (a) regulate trials, with (b) viewing trauma words and not attempting to regulate. Training was followed by one transfer run not involving neurofeedback. Generalized psychophysiological interaction (gPPI) and dynamic causal modeling (DCM) analyses were also computed to explore task‐based functional connectivity and causal structure, respectively. It was found that PTSD patients were able to successfully downregulate both right and left amygdala activation, showing sustained effects within the transfer run. Increased activation in the dorsolateral and ventrolateral prefrontal cortex (PFC), regions related to emotion regulation, was observed during regulate as compared with view conditions. Importantly, activation in the PFC, rostral anterior cingulate cortex, and the insula, were negatively correlated to PTSD dissociative symptoms in the transfer run. Increased functional connectivity between the amygdala‐ and both the dorsolateral and dorsomedial PFC was found during regulate, as compared with view conditions during neurofeedback training. Finally, our DCM analysis exploring directional structure suggested that amygdala downregulation involves both top‐down and bottom‐up information flow with regard to observed PFC‐amygdala connectivity. This is the first demonstration of successful downregulation of the amygdala using rt‐fMRI‐nf in PTSD, which was critically sustained in a subsequent transfer run without neurofeedback, and corresponded to increased connectivity with prefrontal regions involved in emotion regulation during the intervention. Hum Brain Mapp 38:541–560, 2017. © 2016 Wiley Periodicals, Inc.
Evidence‐based HMO care for prostate specific antigen testing
Authors: Merenstein Daniel J. , D'Amico Frank J. , Vinker Shlomo , Petterson Stephen , Lahad Amnon
Published: September 2016

Background

There is pressure in the U.S. system to move away from fee‐for‐service models to a more pre‐paid system, which may result in decreased costs, but the impact on evidence‐based care is unclear. We examined a large pre‐paid Health Maintenance Organizations (HMO) in Israel to see if evidence‐based guidelines are followed for prostate specific antigen (PSA) testing.

Methods

A retrospective cohort of ambulatory visits from 2002 to 2011 of patients age >75 receiving care from Clalit Health Services was conducted. Historically reported U.S. cohorts were used for comparison. The main measure was the percent of patients who had at least one PSA after age 75.

Results

In each of the 10 years of follow‐up, 22% of the yearly Israeli cohort, with no known malignancy or benign prostatic hyperplasia, had at least one PSA, while for the total 10 years, 30% of the men had at least one PSA. These rates are considerably lower than previously reported U.S. rates.

Conclusions

In a pre‐paid system in which physicians have no incentive to order tests, they appear to order PSA tests at a lower rate than has been observed in the U.S. system. Additional quality of measures should continue to be examined as the U.S. shifts away from a fee‐for‐service model. Copyright © 2016 John Wiley & Sons, Ltd.
The Fluorine Gauche Effect: A Brief History
Authors: Thiehoff Christian , Rey Yannick P. , Gilmour Ryan
Published: September 2016

Transforming the fluorine gauche effect from an academic curiosity into a powerful acyclic conformational control strategy has enriched molecular design. This expansive approach to modulating structure has proven to be particularly valuable in the construction of functional small molecules, thereby finding application in diverse disciplines, ranging from therapeutic medicine to enantioselective catalysis. In contrast to the well‐established arsenal of conformational control tactics, in which conformer populations result from minimising nonbonding interactions, (e.g., A1,3‐ or A1,2‐strain), the fluorine gauche effect is attributable to stabilising interactions comprised of two components: stereoelectronic and electrostatic. Conformer populations are partially determined by favourable, hyperconjugative interactions involving proximal electron‐rich σ‐bonds, π‐systems, and nonbonding electron pairs with the antibonding orbital of the C−F σ‐bond: σ→σ*, π→σ*, and n→σ*, respectively. Electrostatic, charge‐dipole interactions (e.g., N+⋅⋅⋅Fδ−) also play a crucial role in stabilising what are often counter‐intuitive conformations. These noncovalent interactions, permissible on account of the low van der Waals radius and high electronegativity of the fluorine atom, render this effect fundamentally important and practically valuable in structural chemistry. In this contribution to the Rosarium Philosophorum in honour of Prof. Jack David Dunitz FRS, we endeavour to delineate, albeit in an abridged form, the evolution of the fluorine gauche effect from a fundamental spectroscopic study to a ubiquitous component of physical organic chemistry.
RGDfK‐functionalized gold nanorods bind only to activated platelets
Authors: Zeller Meidell Krystin , Robinson Ryan , Vieira‐de‐Abreu Adriana , Gormley Adam J. , Ghandehari Hamidreza , W. Grainger David , A. Campbell Robert
Published: September 2016

Integrin‐targeting peptide RGDfK‐labeled gold nanorods (GNR) seek to improve hyperthermia targeted to solid tumors by exploiting the known up‐regulation of integrin αvβ3 cell membrane proteins on solid tumor vasculature surfaces. Tumor binding specificity might be expected since surrounding tissues and endothelial cells have limited numbers of these receptors. However, RGD peptide binding to many proteins is promiscuous, with known affinity to several families of cell integrin receptors, and also possible binding to platelets after intravenous infusion via a different integrin receptor, αIIbβ3, on platelets. Binding of RGDfK‐targeted GNR could considerably impact platelet function, ultimately leading to increased risk of bleeding or thrombosis depending on the degree of interaction. We sought to determine if RGDfK‐labeled GNR could interact with platelets and alter platelet function. Targeted and untargeted nanorods exhibited little interaction with resting platelets in platelet rich plasma (PRP) preparations. However, upon platelet activation, peptide‐targeted nanorods bound actively to platelets. Addition of RGDfK‐GNR to unactivated platelets had little effect on markers of platelet activation, indicating that RGDfK‐nanorods were incapable of inducing platelet activation. We next tested whether activated platelet function was altered in the presence of peptide‐targeted nanorods. Platelet aggregation in whole blood and PRP in the presence of targeted nanorods had no significant effect on platelet aggregation. These data suggest that RGDfK‐GNR alone have little impact on platelet function in plasma. However, nonspecific nanorod binding may occur in vascular beds where activated platelets are normally cleared, such as the spleen and liver, producing a possible toxicity risk for these nanomaterials. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 209–217, 2017.
Correlations Between Bone Mechanical Properties and Bone Composition Parameters in Mouse Models of Dominant and Recessive Osteogenesis Imperfecta and the Response to Anti-TGF-β Treatment
Authors: Bi Xiaohong , Grafe Ingo , Ding Hao , Flores Rene , Munivez Elda , Jiang Ming Ming , Dawson Brian , Lee Brendan , Ambrose Catherine G
Published: September 2016

Osteogenesis imperfecta (OI) is a group of genetic disorders characterized by brittle bones that are prone to fracture. Although previous studies in animal models investigated the mechanical properties and material composition of OI bone, little work has been conducted to statistically correlate these parameters to identify key compositional contributors to the impaired bone mechanical behaviors in OI. Further, although increased TGF-β signaling has been demonstrated as a contributing mechanism to the bone pathology in OI models, the relationship between mechanical properties and bone composition after anti-TGF-β treatment in OI has not been studied. Here, we performed follow-up analyses of femurs collected in an earlier study from OI mice with and without anti-TGF-β treatment from both recessive (Crtap-/-) and dominant (Col1a2+/P.G610C) OI mouse models and WT mice. Mechanical properties were determined using three-point bending tests and evaluated for statistical correlation with molecular composition in bone tissue assessed by Raman spectroscopy. Statistical regression analysis was conducted to determine significant compositional determinants of mechanical integrity. Interestingly, we found differences in the relationships between bone composition and mechanical properties and in the response to anti-TGF-β treatment. Femurs of both OI models exhibited increased brittleness, which was associated with reduced collagen content and carbonate substitution. In the Col1a2+/P.G610C femurs, reduced hydroxyapatite crystallinity was also found to be associated with increased brittleness, and increased mineral-to-collagen ratio was correlated with increased ultimate strength, elastic modulus, and bone brittleness. In both models of OI, regression analysis demonstrated that collagen content was an important predictor of the increased brittleness. In summary, this work provides new insights into the relationships between bone composition and material properties in models of OI, identifies key bone compositional parameters that correlate with the impaired mechanical integrity of OI bone, and explores the effects of anti-TGF-β treatment on bone-quality parameters in these models. © 2016 American Society for Bone and Mineral Research.
Carbon‐14 radiolabeling and tissue distribution evaluation of MMV390048
Authors: Sonopo Molahlehi S. , Pillay Adushan , Chibale Kelly , Marjanovic‐Painter Biljana , Donini Cristina , Zeevaart Jan R.
Published: September 2016

The antimalarial compound MMV390048 ([14C]‐11) was labeled with carbon‐14 isotope via a 3‐step synthesis. It was obtained in a 15.5% radiochemical overall yield from carbon‐14 labeled methyl iodide with a radiochemical purity of >99%. After single oral administration of [14C]‐11 to albino and pigmented rats its tissue distribution profile was studied. Tissue distribution results showed high local exposure in the GI tract and excretory organs but low exposure of all other tissues. The radioactivity uptake was higher in the eyes of the pigmented rats than in the eyes of the albino rats at all‐time points. The highest accumulation reached in the eyes of the pigmented rats was 0.46% at 6 hours. However, these levels are still very low as compared to the other organs studied. There was very little radioactivity from MMV390048 ([14C]‐11) present in the skin of both the albino and pigmented rats. The results obtained are supportive of further development of MMV390048 as a potential antimalarial compound.
The ethmoid and presphenoid of cetaceans
Authors: Ichishima Hiroto
Published: September 2016

A cribriform plate, a perpendicular plate, and two lateral masses are major components of the ethmoid bone of mammals. Notwithstanding the noticeable bone, virtually sitting in the center of the skull, extensive modifications of the skull of modern cetaceans, especially odontocetes (toothed whales), and the lack of clarity as to what characteristics delimit each element of the ethmoid has made the problem of the nature of the cetacean ethmoid more complicated and elusive than in other, less modified mammals. Furthermore, contention as to whether a perpendicular plate of the ethmoid, or the mesethmoid, exists in all mammals including cetaceans has remained unsettled. In odontocetes, the mesethmoid has been variably identified not only as the osseous nasal septum but also as the mediodorsal region of the posterior wall of the nasal passage below the nasals, as a mass of bone encased by the vomer in front of the osseous nasal cavity at the base of the rostrum, and as a combination of some portions mentioned above. The presence or absence of the mesethmoid in various groups of mammals has attracted the attention of some biologists, and here, I demonstrate that cetaceans have no mesethmoid. The close inspection of the ontogenetic changes of the basicranial elements in cetaceans reveals that a mass of bone ensheathed by the vomer in front, or at the level of the osseous nasal cavity is actually the presphenoid. It is highly likely that in odontocetes the posterior wall of the nasal passages below the nasals consists of the combination of the frontal, the imperforated cribriform plate, the paired ectethmoids, and the vomer, the latter three of which partially concealing the presphenoid dorsally and laterally as the ontogeny proceeds. In contrast, mysticetes clearly display ethmoturbinates and a cribriform plate, which are morphologically similar to those in terrestrial mammals. J. Morphol. 277:1661–1674, 2016. © 2016 Wiley Periodicals, Inc.
Identifying abrupt changes and detecting gradual trends of annual rainfall in an Indian arid region under heightened rainfall rise regime
Authors: Machiwal Deepesh , Kumar Sanjay , Dayal Devi , Mangalassery Shamsudheen
Published: September 2016

This study aimed at identification of abrupt change points (CPs) and detection of gradual trends in 34‐year (1980–2013) annual rainfall at nine stations of an Indian arid region. TheCPswere determined by five tests and their significance was examined by two tests. Furthermore, trends were tested by three tests and their magnitudes were quantified by two tests. Novelty of the study lies in investigating significance of trends sequentially over years by applying Mann–Kendall (M–K) test. The identifiedCPswere similar for standard normal homogeneity test and cumulative deviations test at most stations. In contrast, Pettitt and Bayesian tests detectedCPin years 2002 and 2005 at six and three stations, respectively, and their significance was verified. Results of sequential M–K test did not match with other tests' results. The mean annual rainfall afterCP(350–627 mm) increased by 14–80% of the amount beforeCP(306–444 mm) with 7–42% reduction in coefficient of variation. The box–whisker plots supported these findings. Results of trend tests indicated statistically significant trends at Anjar, Bhachau, Mandvi and Rapar. Trend magnitudes by linear regression prior toCP(−6.2 to 7.1 mm year−1) showed an overall increase afterCP(4.7–40.8 mm year−1) with negative trend at one station. Sen's slope test, showing good harmony with linear regression, revealed that trend magnitudes afterCPwere 2–10 times higher than that for 34‐year period at six stations. Results of M–K test applied for sequential periods emphasized that rainfall trends are becoming stronger over time. This finding suggests that significance level of increasing rainfall trends may further increase in future. Finally, findings of this study are useful for planners and decision makers for developing policies to meet the challenges of the heightened rainfall in study area. Also, the approach used here may be adopted in other parts of the globe.
Responses of spring phenology in a fruit tree species (Pyrus sp. cv. Pingguoli) to the changes in surface air temperature in Northeast China
Authors: Shen Yinyue , Kobayashi Kazuhiko
Published: September 2016

We analysed records of spring phenological events (budding and flowering) of pear (Pyrus sp.) cultivar ‘Pingguoli’ at six sites in the Yanbian District of Jilin Province, northeast China across 58 years from 1953. The aims of this study were to test if the phenological timing in spring has changed due to the long‐term change in surface air temperature and to see if the relationship between the phenological timing and the surface air temperature shows nonlinearity as suggested by a past study. We fitted a linear model of phenological timing as the sum of the effects of long‐term temperature trends and year‐to‐year temperature fluctuations. The results showed that the acceleration of spring phenology can be attributed to the corresponding trends of increasing mean air temperature in spring. The relationship between air temperature and phenological timing was linear for budding, but it was nonlinear for flowering with a lower temperature sensitivity at higher air temperature.
Late Quaternary glacial history of the Nalati Range, central Tian Shan, China, investigated using 10Be surface exposure dating
Authors: Zhang Mei , Chen Yixin , Li Yingkui , Liu Gengnian
Published: September 2016

We constrained glacial chronologies in three valleys on the southern slopes of the Nalati Range in the central Tian Shan, China: the Takelakete, Aiken and Sairenwuxunsala valleys, using 10Be surface exposure dating. Our 10Be exposure ages constrain three glacial events during 72.8 ± 3.8–59.9 ± 3.5 ka, 55.4 ± 3.0–34.9 ± 2.1 and 0.29 ± 0.17–0.27 ± 0.20 ka, corresponding to Marine Oxygen Isotope Stages (MIS) 4 and 3, and Little Ice Age (LIA), respectively. Glaciers have been restricted from composite valley glaciers and piedmont glaciers during MIS 4–3 to confined valley glaciers during MIS 3, to small valley glaciers during the LIA, and to hanging and cirque glaciers at present. This pattern of glacial change is broadly consistent with other glaciated areas across the Tian Shan. Extensive glacial advances during MIS 4 and 3 were probably driven by enhanced precipitation brought by the westerlies. Compared to MIS 3 glacial advance, lower temperature may counteract the effect of relatively lower precipitation to drive a similar or even larger glacial advance during MIS 4. Glacial advances were limited during MIS 2, probably reflecting enhanced arid conditions in the Tian Shan caused by the weakened westerlies and strengthened Siberian High.
Comparison of reduced sugar high quality chocolates sweetened with stevioside and crude stevia ‘green’ extract
Authors: Torri Luisa , Frati Alessandra , Ninfali Paolino , Mantegna Stefano , Cravotto Giancarlo , Morini Gabriella
Published: September 2016

BACKGROUND

The demand for zero and reduced‐sugar food products containing cocoa is expanding continuously. The present study was designed to evaluate the feasibility of producing high‐quality chocolate sweetened with a crude extract of Stevia rebaudiana (Bertoni) prepared by a green microwave‐assisted water‐steam extraction procedure. Seven approximately isosweet chocolate formulations were developed, mixing cocoa paste, sucrose, commercial stevioside, crude green extract and maltitol in different proportions. All samples were analyzed for the determination of polyphenol and flavonoid content, antioxidant activity, and sensory acceptability.

RESULTS

The use of a crude stevia extract allowed low‐sugar, high‐quality chocolates to be obtained that were also acceptable by consumers and had a significant increased antioxidant activity. Moreover, consumers' segmentation revealed a cluster of consumers showing the same overall liking for the sample with 50% sucrose replaced by the stevia crude extract as that obtained with the commercial stevioside and the control sample (without sucrose replacement).

CONCLUSION

The results provide information that can contribute to promoting the development of sweet food products, with advantages in terms of an improved nutritional value (reduced sugar content and increased antioxidant activity) and a reduced impact of the production process on the environment. © 2016 Society of Chemical Industry
Trapping Dynamic Disulfide Bonds in the Hard Segments of Thermoplastic Polyurethane Elastomers
Authors: Zhang Longhe , Chen Lifeng , Rowan Stuart J.
Published: September 2016

Dynamic covalent bonds placed within a polymer chain result in stimulus‐responsive materials where the breaking/making and/or exchange of the dynamic bonds controls the response. A key attribute to access such properties is the molecular mobility of the dynamic bonds. The focus of this work is to understand how incorporating a dynamic bond, in the form of disulfide bonds, into the hard phase of a polyurethane will impact the properties of the materials. Thus, uncross‐linked polyurethanes with aliphatic disulfide‐containing hard segments are synthesized via a two‐step protocol, using 2,2′‐dithiodiethanol and/or 1,4‐butanediol in the second step as the chain extenders. Thermomechanical studies show that, if the dynamic bonds are selectively placed in the hard phase of the polyurethane, the dynamic nature of the disulfide bond can be effectively “switched‐off” below the melting temperature of the hard phase. As such the dynamic and mechanical properties of the materials can be controlled by tailoring the nature of the hard phase.

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RAFT‐Polymerization‐Induced Self‐Assembly and Reorganizations: Ultrahigh‐Molecular‐Weight Polymer and Morphology‐Tunable Micro‐/Nanoparticles in One Pot
Authors: Zhang Xiao‐Yun , Liu Dong‐Ming , Lv Xin‐Hu , Sun Miao , Sun Xiao‐Li , Wan Wen‐Ming
Published: September 2016

A one‐pot method is introduced for the successful synthesis of narrow‐distributed (Đ = 1.22) vinyl polymer with both ultrahigh molecular weight (UHMW) (M
w = 1.31 × 106 g mol−1) and micro‐/nanomorphology under mild conditions. The method involves the following four stages: homogeneous polymerization, polymerization‐induced self‐assembly (PISA), PISA and reorganization, and PISA and multiple reorganizations. The key points to the production of UHMW polystyrene are to minimize radical termination by segregating radicals in different nanoreactors and to ensure sufficient chain propagation by promoting further reorganizations of these reactors in situ. This method therefore endows polymeric materials with the outstanding properties of both UHMW and tunable micro‐/nanoparticles under mild conditions in one pot.

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Down‐regulation of β‐catenin and the associated migration ability by Taiwanin C in arecoline and 4‐NQO‐induced oral cancer cells via GSK‐3β activation
Authors: Hsieh Cheng‐Hong , Hsu Hsi‐Hsien , Shibu Marthandam Asokan , Day Cecilia‐Hsuan , Bau Da‐Tian , Ho Chih‐Chu , Lin Yueh‐Min , Chen Ming‐Cheng , Wang Shu‐Huai , Huang Chih‐Yang
Published: September 2016

Cancer is one of the leading causes of death worldwide, and oral squamous cell carcinoma (OSCC) accounts for almost a sixth of all reported cancers. Arecoline, from areca nut is known to enhance carcinogenesis in oral squamous cells. The objective of this study is to determine the effect of Taiwanin C, from Taiwania cryptomerioides Hayata against Arecoline‐associated carcinogenesis. An OSCC model was created in C57BL/6J Narl mice by administrating 0.5 mg mL−1 arecoline with 0.2 mg mL−1 4‐NQO carcinogen for 8 and 28 wk to mimic the etiology of oral cancer patients in Asia. Mice were sacrificed and two cell lines, T28 from the tumor and N28 cancerous cell line from the surrounding non tumor area, were established. Taiwanin C showed effective anti‐tumor activity in nude mice models. Taiwanin C significantly inhibited the cell viability of T28 cells in a dose dependent manner, but did not inflict any effect on N28 normal cells. Taiwanin C treatment inhibited the migration ability of T28 cells in a dose dependent manner as determined by wound healing and migration assays. Taiwanin C also reduced the levels of β‐catenin and its downstream metastatic proteins, Tbx3 and c‐Myc. Besides, Taiwanin C inhibited the nuclear accumulation of β‐catenin and induced β‐catenin degradation via proteasome‐mediated pathway. Moreover, Taiwanin C enhanced GSK‐3β and reduced the p‐ser9 GSK‐3β protein level to inactivate Wnt signaling. Taken together, Taiwanin C blocked the cell migration effects of T28 cells mediated through the activation of GSK‐3β to enhance protein degradation and reduce nuclear accumulation of β‐catenin. © 2016 Wiley Periodicals, Inc.
KITENIN functions as a fine regulator of ErbB4 expression level in colorectal cancer via protection of ErbB4 from E3‐ligase Nrdp1‐mediated degradation
Authors: Sun Eun Gene , Lee Kyung Hwa , Ko Yoo‐Seung , Choi Hui Jeong , Yang Jung‐In , Lee Jae Hyuk , Chung Ik Joo , Paek Yun‐Woong , Kim Hangun , Bae Jeong A , Kim Kyung Keun
Published: September 2016

Understanding the complex biological functions of E3‐ubiquitin ligases may facilitate the development of mechanism‐based anti‐cancer drugs. We recently identified that the KITENIN/ErbB4‐Dvl2‐c‐Jun axis works as a novel unconventional downstream signal of epidermal growth factor (EGF) in colorectal cancer (CRC) tissues. Here we addressed whether E3‐ubiquitin ligases are required for operation of this axis. We found that Nrdp1, an E3‐ligase for ErbB3/ErbB4, interacted with KITENIN (KAI1 C‐terminal interacting tetraspanin) to form a functional KITENIN/ErbB4/Nrdp1 complex and is responsible for down‐regulating Dvl2 within this complex. Interestingly, ErbB4 was resistant to degradation by Nrdp1 in KITENIN/Nrdp1‐co‐transfected CRC cells, and KITENIN bound to the C‐terminal coiled‐coil domain of Nrdp1. Chemical blockade of ErbB kinase did not block the action of EGF to increase in total/phospho‐ErbB4 and phospho‐ERK in KITENIN/ErbB4‐cotransfected cells, whereas it blocked the action of EGF in ErbB4 alone‐transfected CRC cells. In human CRC tissues, higher expressions of ErbB4 and KITENIN and lower expression of Dvl2 was observed in stage IV samples than in stage I, but a low level of Nrdp1 was expressed in both stages and it did not differ significantly by stage. These results indicated that Nrdp1 is necessary for the reduction in Dvl2 to generate c‐Jun in the EGF‐KITENIN/ErbB4‐c‐Jun axis, but more importantly, elevated KITENIN protects KITENIN‐bound ErbB4 from Nrdp1‐mediated degradation via physical collaboration between the KITENIN/ErbB4 complex and Nrdp1, but not via modulation of ErbB kinase activity. Thus, KITENIN functions in the maintenance of a higher expression level of ErbB4 in advanced CRC tissues, independent of ubiquitin‐mediated degradation via Nrdp1. © 2016 Wiley Periodicals, Inc.
Painful Charcot–Marie–Tooth neuropathy type 2E/1F due to a novel NEFL mutation
Authors: Doppler Kathrin , Kunstmann Erdmute , Krüger Stefan , Sommer Claudia
Published: September 2016

Introduction

Charcot–Marie–Tooth neuropathy (CMT) 2E/1F is caused by mutations in the neurofilament light‐chain polypeptide (NEFL) gene. Giant axons are a histological hallmark frequently seen in nerves of patients with CMT2E.

Methods

We describe the case of a 43‐year‐old patient with a painful, predominantly sensory neuropathy.

Results

The patient's sural nerve biopsy showed multiple giant axons. Genetic sequencing of the NEFL gene revealed that the patient was heterozygous for an altered sequence of the gene, c.816C>G, p.Asn272Lys, which has not yet been described in CMT2E/1F.

Conclusion

In contrast to other cases of CMT2E/1F, where motor symptoms are predominant, pain was the most disabling symptom in this patient. Muscle Nerve 55: 752–755, 2017
A GWAS follow‐up of obesity‐related SNPs in SYPL2 reveals sex‐specific association with hip circumference
Authors: de Toro‐Martín J. , Guénard F. , Tchernof A. , Deshaies Y. , Pérusse L. , Biron S. , Lescelleur O. , Biertho L. , Marceau S. , Vohl M.‐C.
Published: September 2016

Objective

A novel single‐nucleotide polymorphism (SNP) associated with morbid obesity was recently identified by exome sequencing. The purpose of this study was to follow up this low‐frequency coding SNP located within the SYPL2 locus and associated with body mass index in order to reveal novel associations with obesity‐related traits.

Methods

The body mass index‐associated SNP (rs62623713 A>G [chr1:109476817/hg19]) and two tagging SNPs within the SYPL2 locus, rs9661614 T>C (chr1:109479215) and rs485660 G>A (chr1:109480810), were genotyped in the obesity (n = 3,017) and the infogene (n = 676) cohorts, which were further combined, leading to a larger cohort of 3,693 individuals. Association testing was performed by general linear models in the obesity cohort and validated by joint analysis in the combined cohort.

Results

rs9661614 and rs485660 were significantly associated with hip circumference (HC) in the obesity cohort, with heterozygotes exhibiting a significantly lower HC. These results were validated by joint analysis for rs9661614 (false discovery rate [FDR]‐corrected P = 7.5 × 10−4) and, to a lesser extent, for rs485660 (FDR corrected P = 3.9 × 10−2). The association with HC remained significant for rs9661614 when tested independently in women (FDR‐corrected P = 1.7 × 10−2), but not for rs485660 (FDR‐corrected P = 0.2). Both associations were absent in men.

Conclusions

This study reveals strong evidence for a novel association between rs9661614 (T>C) and HC in women, which likely reflects a preferential association of SYPL2 to a gynoid profile of fat distribution. The study findings support a clinical significance of SYPL2 worth considering when assessing risk factors associated with obesity.
Aligned poly (glycolide‐lactide) fiber membranes with conducting polypyrrole
Authors: Guo Huiling , Qiao Tiankui , Jiang Suchen , Li Tongguo , Song Ping , Zhang Baochang , Song Xiaofeng
Published: September 2016

Electroactive polypyrrole (PPy) are highly attractive for a number of biomedical applications such as tissue engineering. To improve interfacial compatibility of PPy with biopolyesters, poly (ɛ‐caprolactone) grafted PPy (PPy‐g‐PCL) are synthesized in this work and characterized with Fourier transform infrared and nuclear magnetic resonance. PPy‐g‐PCL exhibits good conductivity and electrochemical activity. It is also blended with poly (glycolide‐lactide) to make aligned fiber membranes via drum at the speed of 1500 r/min. The relationships of blending ratio with the fibrous structure, thermal stability, wettability, and mechanical properties are clarified. The results show that blending PPy‐g‐PCL has no significant effect on the fibrous morphology, but fibers trends aligned architecture as the blend ratio of poly (glycolide‐lactide)/PPy‐g‐PCL exceeds 70/30. The membranous thermal and mechanical stability are modified. The membranous hydrophilicity significantly enhances with PPy‐g‐PCL amount increasing. Then the fiber membrane with topographical and electrical cues is qualified as the application of tissue engineering. Copyright © 2016 John Wiley & Sons, Ltd.