bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary Glycemic Index and Glycemic Load Are Positively Associated with Risk of Developing Metabolic Syndrome in Middle‐Aged and Elderly Adults
Authors: Juanola‐Falgarona Martí , Salas‐Salvadó Jordi , Buil‐Cosiales Pilar , Corella Dolores , Estruch Ramón , Ros Emili , Fitó Montserrat , Recondo Javier , Gómez‐Gracia Enrique , Fiol Miquel , Lapetra José , Lamuela‐Raventós Rosa M. , Serra‐Majem Lluis , Pintó Xavier , Muñoz Miguel A. , Ruiz‐Gutiérrez Valentina , Alfredo Martínez José , Castro‐Quezada Itandehui , Bulló Mònica
Published: October 2015

Objectives

To evaluate how glycemic index (GI) and glycemic load (GL) are associated with the metabolic syndrome (MetS) and its features in middle‐aged and elderly adults at high cardiovascular risk.

Design

Prospective, longitudinal, population‐based cohort.

Setting

PREvención con DIeta MEDiterránea study.

Participants

Men and women (N = 6,606) divided into three age groups (<65, 65–74, ≥75).

Measurements

Energy and nutrient intake was evaluated using a validated 137‐item food frequency questionnaire. MetS and its features were defined in accordance with the criteria of the American Heart Association and National Heart, Lung, and Blood Institute.

Results

A positive association was observed between GI and MetS prevalence in the youngest and middle age groups for participants without diabetes mellitus, but no relationship was found for those with diabetes mellitus. During the median follow‐up of 4.8 years, higher GI and GL were related to greater risk of MetS in the middle age group, independent of the presence of diabetes mellitus. Changes in dietary GI were associated with risk of developing the high fasting glucose component of the MetS in the oldest age category, and changes in dietary GL were associated with risk of developing abdominal obesity, hypertriglyceridemia, low high‐density lipoprotein cholesterol, and high blood pressure in the youngest age category.

Conclusion

Dietary GI and GL have a potential role in the development of MetS and associated clinical features, with particular age‐dependent considerations.
Nerve growth factor (NGF) and pro‐NGF increase low‐density lipoprotein (LDL) receptors in neuronal cells partly by different mechanisms: role of LDL in neurite outgrowth
Authors: Do Hai Thi , Bruelle Céline , Pham Dan Duc , Jauhiainen Matti , Eriksson Ove , Korhonen Laura T. , Lindholm Dan
Published: October 2015

Low‐density lipoprotein receptors (LDLRs) mediate the uptake of lipoprotein particles into cells, as studied mainly in peripheral tissues. Here, we show that nerve growth factor (NGF) increases LDLR levels in PC6.3 cells and in cultured septal neurons from embryonic rat brain. Study of the mechanisms showed that NGF enhanced transcription of the LDLR gene, acting mainly via Tropomyosin receptor kinase A receptors. Simvastatin, a cholesterol‐lowering drug, also increased the LDLR expression in PC6.3 cells. In addition, pro‐NGF and pro‐brain‐derived neurotrophic factor, acting via the p75 neurotrophin receptor (p75NTR) also increased LDLRs. We further observed that Myosin Regulatory Light Chain‐Interacting Protein/Inducible Degrader of the LDLR (Mylip/Idol) was down‐regulated by pro‐NGF, whereas the other LDLR regulator, proprotein convertase subtilisin kexin 9 (PCSK9) was not significantly changed. On the functional side, NGF and pro‐NGF increased lipoprotein uptake by neuronal cells as shown using diacetyl‐labeled LDL. The addition of serum‐derived lipoprotein particles in conjunction with NGF or simvastatin enhanced neurite outgrowth. Collectively, these results show that NGF and simvastatin are able to stimulate lipoprotein uptake by neurons with a positive effect on neurite outgrowth. Increases in LDLRs and lipoprotein particles in neurons could play a functional role during brain development, in neuroregeneration and after brain injuries.

image

Nerve growth factor (NGF) and pro‐NGF induce the expression of low‐density lipoprotein receptors (LDLRs) in neuronal cells leading to increased LDLR levels. Pro‐NGF also down‐regulated myosin regulatory light chain‐interacting protein/inducible degrader of the LDLR (Mylip/Idol) that is involved in the degradation of LDLRs. NGF acts mainly via Tropomyosin receptor kinase A (TrkA) receptors, whereas pro‐NGF stimulates p75 neurotrophin receptor (p75NTR). Elevated LDLRs upon NGF and pro‐NGF treatments enhanced lipoprotein uptake by neurons. Addition of LDL particles further led to the stimulation of neurite outgrowth in PC6.3 cells after NGF or simvastatin treatments, suggesting a stimulatory role of lipoproteins on neuronal differentiation. In contrast, pro‐NGF had no effect on neurite outgrowth either in the absence or presence of LDL particles. The precise mechanisms by which increased lipoproteins uptake can affect neurite outgrowth warrant further studies.
Vaginoplasty in Male-to-Female Transsexual Surgery: A Training Concept Incorporating Dissection Room Experience to Optimize Functional and Cosmetic Results
Authors: Leclère F. M. , Casoli V. , Weigert R.
Published: October 2015

Introduction

Learning a new technique, even for an established surgeon, requires a learning curve; however, in transsexual surgery especially, there is a lack of professional and public tolerance for suboptimal aesthetic and functional results due to a learning curve.

Aims

In this context, we have tried to build a learning concept for vaginoplasty that includes four steps: (i) formal identification of the surgical steps in order to provide both measure of surgical process and measures of outcomes; (ii) training on cadavers with expert assistance; (iii) performing the live surgery with assistance from expert; and (iv) performing the surgery alone. Herein, we emphasize the second step of our learning concept.

Material and Methods

Between September 2013 and December 2013, 15 cadavers were operated on by an established surgeon learning vaginoplasty under assistance from two expert practitioners. Mean global time and mean time necessary to perform each step of the operation were recorded by the experts. Intraoperative complications were systematically registered. The final depth and diameter of the neaovaginal cavity were precisely measured. For each cadaver, the aesthetic results were assessed by one of the experts.

Results

Mean total operating time was 179 ± 34 minutes and decreased from 262 minutes for the first training attempt to 141 minutes for the last one. Intraoperative expert correction included modification of the scrotal triangular flap design and change of position of the urethra: This happened during the first training. No lesion of the urethra or of the anus occurred. The two experts judged the outcomes as excellent in seven cases, very good in four cases, good in two cases, and fair in two cases.

Conclusion

Despite the numerous reports on vaginoplasty in the literature, there is a real lack of published information on the learning curve of this operation. We make the hypothesis that introducing a learning concept with assistance from expert practitioners at the beginning of the surgeon's experience can optimize both the duration of his learning curve and reduce the risk of major complications.
Leishmania donovani‐specific Ub‐related modifier‐1: an early endosome‐associated ubiquitin‐like conjugation in Leishmania donovani
Authors: Sharma Vanila , Sharma Paresh , Selvapandiyan Angamuthu , Salotra Poonam
Published: October 2015

Protein modification by ubiquitin (Ub) and Ub‐like molecules (Ubls) is a diverse biological process that regulates the activity of the target proteins. Systematic studies of Ubls in trypanosomatids like Leishmania, the causative organism of potentially fatal visceral leishmaniasis, would yield a better understanding of the disease pathogenesis and identify novel therapeutic targets. The present study is the first to characterize Leishmania donovani‐specific Ub‐related modifier‐1 (LdUrm1) and the associated conjugation pathway. Based on homology modeling, LdUrm1 was found to possess a β‐grasp fold and a C‐terminal di‐glycine motif unique to Ub/Ubls, essential for its conjugation to the target proteins. We identified LdUba4 as the E1 enzyme for LdUrm1 and demonstrated its energy‐dependent enzymatic activity. LdUrm1 was immunolocalized anteriorly near the flagellar reservoir, while LdUba4 was cytoplasmic, both in promastigotes and axenic amastigotes. Expression of nonconjugatable LdUrm1 in L. donovani resulted in depleted parasite growth suggesting its role in the pathogenesis. By mass spectrometry, we identified Rab5, a known mediator of early endosome regulated hemoglobin endocytosis in Leishmania, as a target of LdUrm1. Our data suggest that LdUrm1 conjugation pathway may have a role in early endosome‐mediated heme uptake in Leishmania that may be explored as a drug target.
Simple renal cyst and renal dysfunction: A pilot study using dimercaptosuccinic acid renal Scan
Authors: Kwon Taekmin , Lim Bumjin , You Dalsan , Hong Bumsik , Hong Jun Hyuk , Kim Choung‐Soo , Jeong In Gab
Published: October 2015

Aim

Little is known about the association between renal cyst and renal dysfunction. We evaluated the deterioration of renal function in patients with unilateral, large, simple renal cysts.

Methods

Fifty patients with unilateral, simple renal cysts measuring ≥ 4 cm (cyst group) and 50 kidney donors (control group) were enrolled. Dimercaptosuccinic acid (DMSA) renal scans were performed to calculate split renal function. The differences between split renal function were calculated and compared. Clinical factors affecting decreased renal function in the cyst group were assessed.

Results

The mean age of the patients in the cyst group was higher than the control group (59.1 vs 39.2 years; P = 0.001). Patients with renal cysts tended to be diagnosed with hypertension (P = 0.001), However, the two groups did not significantly differ in terms of the other characteristics. The median cyst size was 7.2 cm (range, 4.5–14.2), and 31 of the 50 patients (60.2%) in the cyst group demonstrated decreased renal function in the cystic kidney units (median: 5.8%; range, 0.2–33). Although there were no differences in split renal function (50.1% vs 49.9%; P = 0.629) in the control group, the relative renal function of the cystic kidney units were significantly lower than the contralateral kidney units in the cyst group (48.3% vs 51.7%; P = 0.001). The decrease in relative renal function (>8%) in the cystic kidney units was associated with a higher serum uric acid levels and higher RENAL complexity (P = 0.035 and P = 0.007, respectively).

Conclusion

A significant proportion of unilateral, large, simple renal cysts are associated with decreased relative renal function on DMSA renal scans.
Tobin Tax and Volatility: A Threshold Quantile Autoregressive Regression Framework
Authors: Damette Olivier , Park Beum‐Jo
Published: October 2015

From an original data set on the euro–dollar and on the won–dollar currency pairs (2008–2010), we conduct a threshold quantile autoregressive model to explain the role of aTobin tax (TT) on the exchange rate volatility, taking into account two types of nonlinearity (regimes and quantiles). We find evidence that the impact of aTTwould not be monotonic. ATTmay be a good instrument to stabilize foreign exchange volatility only in normal times and/or in efficient markets. In contrast, aTTcould be counterproductive in turbulent periods by increasing the volatility. In addition, by comparing a major currency pair (euro/dollar) and a minor currency pair (won/dollar), it appears that the potential stabilizing effect of aTTwould be more clear‐cut in the low volatility regime of a major currency pair, similar to the euro/dollar. Our results do not corroborate the previous studies that derived a monotonic and positive impact of aTTon volatility.
Tariff Liberalization and Trade Integration of Emerging Countries
Authors: Disdier Anne‐Célia , Fontagné Lionel , Mimouni Mondher
Published: October 2015

This paper investigates how tariff liberalization has affected exporting at the product‐destination level in emerging countries. We use a highly disaggregated (six‐digit level of the harmonized system—HS—classification) bilateral measure of market access to compare tariffs applied in 1996 and 2006, which includes the timing of the Uruguay Round and episodes of bilateral liberalization. Our econometric estimations consider impacts of tariff cuts on three components of the trade margins: extensive margin of entry (new trade relationships at the product‐destination level), extensive margin of exit (disappearance of existing relationships) and intensive margin of trade (deepening existing relationships). Our main estimates indicate that a reduction of bilateral applied tariffs of 1 percentage point increases the extensive margin of entry by 0.1% and the intensive one by 2.09%, while it reduces the extensive margin of exit by 0.25%.
Creole Hegemony in Caribbean Societies: The Case of Suriname
Authors: Gowricharn Ruben
Published: October 2015

Evaluating the representation of the East Indian communities in the national political identity of Caribbean countries, and building on the discussion waged in Guyana and especially Trinidad and Tobago, this article elaborates on the example of Suriname. It argues that the Surinamese example differs from that of other countries in the region with respect to the ample opportunity the Indo‐Surinamese community had to change their exclusion from political representation. A second distinguishing feature of Suriname is the uncontested Creole preponderance. Theoretically, the article differentiates the Gramscian concept of hegemony into contested, resisted, and accepted hegemony in order to capture the relations between the Indian communities and the national political identity. The article argues that part of the difference between these Caribbean countries, and more specifically, part of the self‐restraint on the political agency of the Indian community in Suriname, can be attributed to these countries' ideologies and specific demographic and political constellations.
Ergatives Move Too Early: On an Instance of Opacity in Syntax
Authors: Assmann Anke , Georgi Doreen , Heck Fabian , Müller Gereon , Weisser Philipp
Published: October 2015

We examine the ban on Ā‐movement of the external argument of a transitive verb that holds in many morphologically ergative languages. We argue that the prohibition against movement of the ergative subject should not be derived from restrictions on the movement of the ergative DP. Rather, we suggest that movement of the ergative argument is per se unproblematic, but if it applies, it applies too early and thereby creates problems for its absolutive co‐argument, which does not receive structural case. In morphologically accusative languages, no such movement asymmetry arises because arguments move too late to trigger the fatal consequences that moving ergatives cause. We present a co‐argument‐based analysis that implies a strictly derivational syntax in which the order of operations plays an important role in deriving properties of the grammar. The analysis also involves an instance of syntactic opacity that (all things being equal) cannot be captured by representational means, thus lending support to a derivational approach to syntax.
Centromere and telomere sequence alterations reflect the rapid genome evolution within the carnivorous plant genus Genlisea
Authors: Tran Trung D. , Cao Hieu X. , Jovtchev Gabriele , Neumann Pavel , Novák Petr , Fojtová Miloslava , Vu Giang T.H. , Macas Jiří , Fajkus Jiří , Schubert Ingo , Fuchs Joerg
Published: October 2015

Linear chromosomes of eukaryotic organisms invariably possess centromeres and telomeres to ensure proper chromosome segregation during nuclear divisions and to protect the chromosome ends from deterioration and fusion, respectively. While centromeric sequences may differ between species, with arrays of tandemly repeated sequences and retrotransposons being the most abundant sequence types in plant centromeres, telomeric sequences are usually highly conserved among plants and other organisms. The genome size of the carnivorous genus Genlisea (Lentibulariaceae) is highly variable. Here we study evolutionary sequence plasticity of these chromosomal domains at an intrageneric level. We show that Genlisea nigrocaulis (1C = 86 Mbp; 2n = 40) and G. hispidula (1C = 1550 Mbp; 2n = 40) differ as to their DNA composition at centromeres and telomeres. G. nigrocaulis and its close relative G. pygmaea revealed mainly 161 bp tandem repeats, while G. hispidula and its close relative G. subglabra displayed a combination of four retroelements at centromeric positions. G. nigrocaulis and G. pygmaea chromosome ends are characterized by the Arabidopsis‐type telomeric repeats (TTTAGGG); G. hispidula and G. subglabra instead revealed two intermingled sequence variants (TTCAGG and TTTCAGG). These differences in centromeric and, surprisingly, also in telomeric DNA sequences, uncovered between groups with on average a > 9‐fold genome size difference, emphasize the fast genome evolution within this genus. Such intrageneric evolutionary alteration of telomeric repeats with cytosine in the guanine‐rich strand, not yet known for plants, might impact the epigenetic telomere chromatin modification.
Effect of Microstructure on Electromigration-Induced Stress
Authors: Maniatty Antoinette M. , Ni Jiamin , Liu Yong , Zhang Hongqing
Published: October 2015

In this paper, a finite element based simulation approach for predicting the effect of microstructure on the stresses resulting from electromigration-induced diffusion is described. The electromigration and stress-driven diffusion equation is solved coupled to the mechanical equilibrium and elastic constitutive equation, where a diffusional inelastic strain is introduced. Here, the focus is on the steady state, infinite life case, when the current-driven diffusion is balanced by the resulting stress gradient. The effect of the crystal orientation in Sn-based solder joints on the limiting current density for an infinite life is investigated and compared to experimental observations in the literature. The effect of the grain structure for Al interconnect lines on the dominant diffusion path and estimates for the effective charge number for two different diffusion paths in Al interconnects determined by matching simulations to experimental measurements of elastic strain components in the literature are also presented.
Fuzzy Generalized Predictive Control for Nonlinear Brushless Direct
Current Motor
Authors: Wang Bin , Shi Ke , Zhang Cheng , Zhu Delan
Published: October 2015

In the study, a novel fuzzy generalized predictive control (GPC) scheme is proposed for the stability control of nonlinear brushless DC motor (BLDCM). First, the fuzzy predictive model of BLDCM is presented via Takagi–Sugeno fuzzy model. Then, based on the controlled autoregressive moving average (CARMA) model transformed by Takagi–Sugeno fuzzy model of BLDCM, a new fuzzy GPC scheme for the nonlinear BLDCM is designed by combining fuzzy techniques and GPC theory, and the rigorous mathematical derivation is given. Finally, numerical simulations are implemented to verify the effectiveness and superiority of the proposed scheme. It also provides reference for other nonlinear even chaos control in actual project.
Lyapunov Stability of Noncommensurate Fractional Order Systems: An Energy Balance Approach
Authors: Trigeassou Jean-Claude , Maamri Nezha , Oustaloup Alain
Published: October 2015

Lyapunov stability of linear noncommensurate order fractional systems is treated in this paper. The proposed methodology is based on the concept of fractional energy stored in inductor and capacitor components, where natural decrease of the stored energy is caused by internal Joule losses. The Lyapunov function is expressed as the sum of the different reversible fractional energies, whereas its derivative is interpreted in terms of internal and external Joule losses. Stability conditions are derived from the energy balance principle, adapted to the fractional case. Examples are taken from electrical systems, but this methodology applies also directly to mechanical and electromechanical systems.
A Nonlinear Gain-Scheduling Compensation Approach Using Parameter-Dependent Lyapunov Functions
Authors: Wu Fen , Song Xun , Ren Zhang
Published: October 2015

This paper addresses the gain-scheduling control design for nonlinear systems to achieve output regulation. For gain-scheduling control, the linear parameter-varying (LPV) model is obtained by linearizing the plant about zero-error trajectories upon which an LPV controller is based. A key in this process is to find a nonlinear output feedback compensator such that its linearization matches with the designed LPV controller. Then, the stability and performance properties of LPV control about the zero-error trajectories can be inherited when the nonlinear compensator is implemented. By incorporating the exosystem, nominal input, and measured output information into the LPV model, the LPV control synthesis problem is formulated as linear matrix inequalities (LMIs) using parameter-dependent Lyapunov functions (PDLFs). Moreover, explicit formulae for the construction of the nonlinear gain-scheduled compensator have been derived to meet the linearization requirement. Finally, the validity of the proposed nonlinear gain-scheduling control approach is demonstrated through a ball and beam example.
Differences in Morphology and Traction Generation of Cell Lines Representing Different Stages of Osteogenesis
Authors: Poellmann Michael J. , Estrada Jonathan B. , Boudou Thomas , Berent Zachary T. , Franck Christian , Wagoner Johnson Amy J.
Published: October 2015

Osteogenesis is the process by which mesenchymal stem cells differentiate to osteoblasts and form bone. The morphology and root mean squared (RMS) traction of four cell types representing different stages of osteogenesis were quantified. Undifferentiated D1, differentiated D1, MC3T3-E1, and MLO-A5 cell types were evaluated using both automated image analysis of cells stained for F-actin and by traction force microscopy (TFM). Undifferentiated mesenchymal stem cell lines were small, spindly, and exerted low traction, while differentiated osteoblasts were large, had multiple processes, and exerted higher traction. Size, shape, and traction all correlated with the differentiation stage. Thus, cell morphology evolved and RMS traction increased with differentiation. The results provide a foundation for further work with these cell lines to study the mechanobiology of bone formation.
Endurance Cyclist Fluid Intake, Hydration Status, Thirst, and Thermal Sensations: Gender Differences
Authors: Armstrong Lawrence E. , Johnson Evan C. , McKenzie Amy L. , Ellis Lindsay A. , Williamson Keith H.
Published: October 2015

This field investigation assessed differences (e.g., drinking behavior, hydration status, perceptual ratings) between female and male endurance cyclists who completed a 164-km event in a hot environment (35 °C mean dry bulb) to inform rehydration recommendations for athletes. Three years of data were pooled to create 2 groups of cyclists: women (n = 15) and men (n = 88). Women were significantly smaller (p < .001) than men in height (166 ± 5 vs. 179 ± 7 cm), body mass (64.6 ± 7.3 vs. 86.4 ± 12.3 kg), and body mass index (BMI; 23.3 ± 1.8 vs. 26.9 ± 3.4) and had lower preevent urinary indices of hydration status, but were similar to men in age (43 ± 7 years vs. 44 ± 9 years) and exercise time (7.77 ± 1.24 hr vs. 7.23 ± 1.75 hr). During the 164-km ride, women lost less body mass (−0.7 ± 1.0 vs. −1.7 ± 1.5 kg; −1.1 ± 1.6% vs. −1.9 ± 1.8% of body weight; p < .005) and consumed less fluid than men (4.80 ± 1.28 L vs. 5.59 ± 2.13 L; p < .005). Women consumed a similar volume of fluid as men, relative to body mass (milliliters/kilogram). To control for performance and anthropomorphic characteristics, 15 women were pair-matched with 15 men on the basis of exercise time on the course and BMI; urine-specific gravity, urine color, and body mass change (kilograms and percentage) were different (p < .05) in 4 of 6 comparisons. No gender differences were observed for ratings of thirst, thermal sensation, or perceived exertion. In conclusion, differences in relative fluid volume consumed and hydration indices suggest that professional sports medicine organizations should consider gender and individualized drinking plans when formulating pronouncements regarding rehydration during exercise.
Rapid Weight Loss Among Adolescents Participating In Competitive Judo
Authors: Berkovich Ben-El , Eliakim Alon , Nemet Dan , Stark Aliza Hannah , Sinai Tali
Published: October 2015

Athletes competing in individual sports such as judo are categorized by weight. Before competitions, weight cutting is common. This cross-sectional study was designed to characterize and determine the prevalence of rapid weight loss (RWL) among adolescent judo competitors. Male athletes aged 12- to 17-years old (N = 108) were recruited from local judo teams. Each participant completed a validated questionnaire regarding RWL practices. Anthropometric measurements were also performed. Average age was 14.6 ± 1.6 years and all participants were of normal body mass index (BMI). RWL was practiced by 80% of the athletes before competition, beginning at an average age of 12.5 ± 2.2 years with the highest prevalence (~94%) in the oldest group of judoka (16–17.9 years). Precompetition weight loss duration was 8 ± 5.4 days, with an average weight reduction of 1.5 ± 1.1 kg. The number of weight loss efforts per athlete in the past season was 2.8 ± 2.2. RWL was achieved by increased physical activity (82.6%), skipped meals (56.3%), or fasting at least once (47%). Two-thirds of the athletes indicated that their coaches were the most influential figure in their decision to lose weight before competition. RWL is highly prevalent in adolescent judo competitors. The methods used by these athletes can potentially lead to significant health risks including compromised nutritional status, diminished physical performance and impaired growth and development. It is of great importance to insure that those who guide young adults in weight loss for competitive sports have the knowledge and understanding to make safe recommendations and appropriate decisions regarding achieving specific weight goals.
Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice
Authors: Yamashiro Yoshito , Papke Christina L. , Kim Jungsil , Ringuette Lea-Jeanne , Zhang Qing-Jun , Liu Zhi-Ping , Mirzaei Hamid , Wagenseil Jessica E. , Davis Elaine C. , Yanagisawa Hiromi
Published: October 2015

Aortic aneurysms may form when smooth muscle cells cannot respond appropriately to external mechanical forces.
Structural Basis of Metallo-β-Lactamase Inhibition by Captopril Stereoisomers
Authors: Brem Jürgen , van Berkel Sander S. , Zollman David , Lee Sook Y. , Gileadi Opher , McHugh Peter J. , Walsh Timothy R. , McDonough Michael A. , Schofield Christopher J.
Published: October 2015

β-Lactams are the most successful antibacterials, but their effectiveness is threatened by resistance, most importantly by production of serine- and metallo-β-lactamases (MBLs). MBLs are of increasing concern because they catalyze the hydrolysis of almost all β-lactam antibiotics, including recent-generation carbapenems. Clinically useful serine-β-lactamase inhibitors have been developed, but such inhibitors are not available for MBLs.
l
-Captopril, which is used to treat hypertension via angiotensin-converting enzyme inhibition, has been reported to inhibit MBLs by chelating the active site zinc ions via its thiol(ate). We report systematic studies on B1 MBL inhibition by all four captopril stereoisomers. High-resolution crystal structures of three MBLs (IMP-1, BcII, and VIM-2) in complex with either the
l
- or
d
-captopril stereoisomer reveal correlations between the binding mode and inhibition potency. The results will be useful in the design of MBL inhibitors with the breadth of selectivity required for clinical application against carbapenem-resistant
Enterobacteriaceae
and other organisms causing MBL-mediated resistant infections.
Pharmacokinetic-Pharmacodynamic Model for the Effect of
l
-Arginine on Endothelial Function in Patients with Moderately Severe Falciparum Malaria
Authors: Brussee Janneke M. , Yeo Tsin W. , Lampah Daniel A. , Anstey Nicholas M. , Duffull Stephen B.
Published: October 2015

Impaired organ perfusion in severe falciparum malaria arises from microvascular sequestration of parasitized cells and endothelial dysfunction. Endothelial dysfunction in malaria is secondary to impaired nitric oxide (NO) bioavailability, in part due to decreased plasma concentrations of
l
-arginine, the substrate for endothelial cell NO synthase. We quantified the time course of the effects of adjunctive
l
-arginine treatment on endothelial function in 73 patients with moderately severe falciparum malaria derived from previous studies. Three groups of 10 different patients received 3 g, 6 g, or 12 g of
l
-arginine as a half-hour infusion. The remaining 43 received saline placebo. A pharmacokinetic-pharmacodynamic (PKPD) model was developed to describe the time course of changes in exhaled NO concentrations and reactive hyperemia-peripheral arterial tonometry (RH-PAT) index values describing endothelial function and then used to explore optimal dosing regimens for
l
-arginine. A PK model describing arginine concentrations in patients with moderately severe malaria was extended with two pharmacodynamic biomeasures, the intermediary biochemical step (NO production) and endothelial function (RH-PAT index). A linear model described the relationship between arginine concentrations and exhaled NO. NO concentrations were linearly related to RH-PAT index. Simulations of dosing schedules using this PKPD model predicted that the time within therapeutic range would increase with increasing arginine dose. However, simulations demonstrated that regimens of continuous infusion over longer periods would prolong the time within the therapeutic range even more. The optimal dosing regimen for
l
-arginine is likely to be administration schedule dependent. Further studies are necessary to characterize the effects of such continuous infusions of
l
-arginine on NO and microvascular reactivity in severe malaria.
Alkyl Amine Bevirimat Derivatives Are Potent and Broadly Active HIV-1 Maturation Inhibitors
Authors: Urano Emiko , Ablan Sherimay D. , Mandt Rebecca , Pauly Gary T. , Sigano Dina M. , Schneider Joel P. , Martin David E. , Nitz Theodore J. , Wild Carl T. , Freed Eric O.
Published: October 2015

Concomitant with the release of human immunodeficiency virus type 1 (HIV-1) particles from the infected cell, the viral protease cleaves the Gag polyprotein precursor at a number of sites to trigger virus maturation. We previously reported that a betulinic acid-derived compound, bevirimat (BVM), blocks HIV-1 maturation by disrupting a late step in protease-mediated Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA. BVM was shown in multiple clinical trials to be safe and effective in reducing viral loads in HIV-1-infected patients. However, naturally occurring polymorphisms in the SP1 region of Gag (e.g., SP1-V7A) led to a variable response in some BVM-treated patients. The reduced susceptibility of SP1-polymorphic HIV-1 to BVM resulted in the discontinuation of its clinical development. To overcome the loss of BVM activity induced by polymorphisms in SP1, we carried out an extensive medicinal chemistry campaign to develop novel maturation inhibitors. In this study, we focused on alkyl amine derivatives modified at the C-28 position of the BVM scaffold. We identified a set of derivatives that are markedly more potent than BVM against an HIV-1 clade B clone (NL4-3) and show robust antiviral activity against a variant of NL4-3 containing the V7A polymorphism in SP1. One of the most potent of these compounds also strongly inhibited a multiclade panel of primary HIV-1 isolates. These data demonstrate that C-28 alkyl amine derivatives of BVM can, to a large extent, overcome the loss of susceptibility imposed by polymorphisms in SP1.
Activation of the Classical Mitogen-Activated Protein Kinases Is Part of the Shiga Toxin-Induced Ribotoxic Stress Response and May Contribute to Shiga Toxin-Induced Inflammation
Authors: Jandhyala Dakshina M. , Ahluwalia Amrita , Schimmel Jennifer J. , Rogers Arlin B. , Leong John M. , Thorpe Cheleste M.
Published: October 2015

Infection with enterohemorrhagicEscherichia coli(EHEC) can result in severe disease, including hemorrhagic colitis and the hemolytic uremic syndrome. Shiga toxins (Stx) are the key EHEC virulence determinant contributing to severe disease. Despite inhibiting protein synthesis, Shiga toxins paradoxically induce the expression of proinflammatory cytokines from various cell typesin vitro, including intestinal epithelial cells (IECs). This effect is mediated in large part by the ribotoxic stress response (RSR). The Shiga toxin-induced RSR is known to involve the activation of the stress-activated protein kinases (SAPKs) p38 and JNK. In some cell types, Stx also can induce the classical mitogen-activated protein kinases (MAPKs) or ERK1/2, but the mechanism(s) by which this activation occurs is unknown. In this study, we investigated the mechanism by which Stx activates ERK1/2s in IECs and the contribution of ERK1/2 activation to interleukin-8 (IL-8) expression. We demonstrate that Stx1 activates ERK1/2 in a biphasic manner: the first phase occurs in response to StxB1 subunit, while the second phase requires StxA1 subunit activity. We show that the A subunit-dependent ERK1/2 activation is mediated through ZAK-dependent signaling, and inhibition of ERK1/2 activation via the MEK1/2 inhibitors U0126 and PD98059 results in decreased Stx1-mediated IL-8 mRNA. Finally, we demonstrate that ERK1/2 are activatedin vivoin the colon of Stx2-intoxicated infant rabbits, a model in which Stx2 induces a primarily neutrophilic inflammatory response. Together, our data support a role for ERK1/2 activation in the development of Stx-mediated intestinal inflammation.
Protein Analysis of Sapienic Acid-Treated Porphyromonas gingivalis Suggests Differential Regulation of Multiple Metabolic Pathways
Authors: Fischer Carol L. , Dawson Deborah V. , Blanchette Derek R. , Drake David R. , Wertz Philip W. , Brogden Kim A.
Published: October 2015

Lipids endogenous to skin and mucosal surfaces exhibit potent antimicrobial activity againstPorphyromonas gingivalis, an important colonizer of the oral cavity implicated in periodontitis. Our previous work demonstrated the antimicrobial activity of the fatty acid sapienic acid (C16:1Δ6) againstP. gingivalisand found that sapienic acid treatment alters both protein and lipid composition from those in controls. In this study, we further examined whole-cell protein differences between sapienic acid-treated bacteria and untreated controls, and we utilized open-source functional association and annotation programs to explore potential mechanisms for the antimicrobial activity of sapienic acid. Our analyses indicated that sapienic acid treatment induces a unique stress response inP. gingivalisresulting in differential expression of proteins involved in a variety of metabolic pathways. This network of differentially regulated proteins was enriched in protein-protein interactions (P= 2.98 × 10−8), including six KEGG pathways (Pvalue ranges, 2.30 × 10−5to 0.05) and four Gene Ontology (GO) molecular functions (Pvalue ranges, 0.02 to 0.04), with multiple suggestive enriched relationships in KEGG pathways and GO molecular functions. Upregulated metabolic pathways suggest increases in energy production, lipid metabolism, iron acquisition and processing, and respiration. Combined with a suggested preferential metabolism of serine, which is necessary for fatty acid biosynthesis, these data support our previous findings that the site of sapienic acid antimicrobial activity is likely at the bacterial membrane.

IMPORTANCEP. gingivalisis an important opportunistic pathogen implicated in periodontitis. Affecting nearly 50% of the population, periodontitis is treatable, but the resulting damage is irreversible and eventually progresses to tooth loss. There is a great need for natural products that can be used to treat and/or prevent the overgrowth of periodontal pathogens and increase oral health. Sapienic acid is endogenous to the oral cavity and is a potent antimicrobial agent, suggesting a potential therapeutic or prophylactic use for this fatty acid. This study examines the effects of sapienic acid treatment onP. gingivalisand highlights the membrane as the likely site of antimicrobial activity.
Tobramycin-Treated Pseudomonas aeruginosa PA14 Enhances Streptococcus constellatus 7155 Biofilm Formation in a Cystic Fibrosis Model System
Authors: Price Katherine E. , Naimie Amanda A. , Griffin Edward F. , Bay Charles , O'Toole George A.
Published: October 2015

Cystic fibrosis (CF) is a human genetic disorder which results in a lung environment that is highly conducive to chronic microbial infection. Over the past decade, deep-sequencing studies have demonstrated that the CF lung can harbor a highly diverse polymicrobial community. We expanded our existing
in vitro
model of
Pseudomonas aeruginosa
biofilm formation on CF-derived airway cells to include this broader set of CF airway colonizers to investigate their contributions to CF lung disease, particularly as they relate to the antibiotic response of the population. Using this system, we identified an interspecies interaction between
P. aeruginosa
, a bacterium associated with declining lung function and worsening disease, and
Streptococcus constellatus
, a bacterium correlated with the onset of pulmonary exacerbations in CF patients. The growth rate and cytotoxicity of
S. constellatus
7155 and
P. aeruginosa
PA14 were unchanged when grown together as mixed biofilms in the absence of antibiotics. However, the addition of tobramycin, the frontline maintenance therapy antibiotic for individuals with CF, to a mixed biofilm of
S. constellatus
7155 and
P. aeruginosa
PA14 resulted in enhanced
S. constellatus
biofilm formation. Through a candidate genetic approach, we showed that
P. aeruginosa
rhamnolipids were reduced upon tobramycin exposure, allowing for
S. constellatus
7155 biofilm enhancement, and monorhamnolipids were sufficient to reduce
S. constellatus
7155 biofilm viability in the absence of tobramycin. While the findings presented here are specific to a biofilm of
S. constellatus
7155 and
P. aeruginosa
PA14, they highlight the potential of polymicrobial interactions to impact antibiotic tolerance in unanticipated ways.

IMPORTANCE
Deep-sequencing studies have demonstrated that the CF lung can harbor a diverse polymicrobial community. By recapitulating the polymicrobial communities observed in the CF lung and identifying mechanisms of interspecies interactions, we have the potential to select the best therapy for a given bacterial community and reveal potential opportunities for novel therapeutic interventions. Using an
in vitro
model of bacterial infection on CF airway cells, we tested how a particular polymicrobial community grows, damages human cells, and responds to antibiotics in single and mixed infections. We describe here the mechanism of an interspecies interaction between two pathogens in the CF lung,
P. aeruginosa
and
S. constellatus
, which is potentiated by a commonly prescribed antibiotic, tobramycin.
Robotic, laparoscopic and open surgery for gastric cancer compared on surgical, clinical and oncological outcomes: a multi-institutional chart review. A study protocol of the International study group on Minimally Invasive surgery for GASTRIc Cancer—IMIGASTRIC
Authors: Desiderio Jacopo , Jiang Zhi-Wei , Nguyen Ninh T , Zhang Shu , Reim Daniel , Alimoglu Orhan , Azagra Juan-Santiago , Yu Pei-Wu , Coburn Natalie G , Qi Feng , Jackson Patrick G , Zang Lu , Brower Steven T , Kurokawa Yukinori , Facy Olivier , Tsujimoto Hironori , Coratti Andrea , Annecchiarico Mario , Bazzocchi Francesca , Avanzolini Andrea , Gagniere Johan , Pezet Denis , Cianchi Fabio , Badii Benedetta , Novotny Alexander , Eren Tunc , Leblebici Metin , Goergen Martine , Zhang Ben , Zhao Yong-Liang , Liu Tong , Al-Refaie Waddah , Ma Junjun , Takiguchi Shuji , Lequeu Jean-Baptiste , Trastulli Stefano , Parisi Amilcare
Published: October 2015

Introduction

Gastric cancer represents a great challenge for healthcare providers and requires a multidisciplinary treatment approach in which surgery plays a major role. Minimally invasive surgery has been progressively developed, first with the advent of laparoscopy and recently with the spread of robotic surgery, but a number of issues are currently being debated, including the limitations in performing an effective extended lymph node dissection, the real advantages of robotic systems, the role of laparoscopy for Advanced Gastric Cancer, the reproducibility of a total intracorporeal technique and the oncological results achievable during long-term follow-up.

Methods and analysis

A multi-institutional international database will be established to evaluate the role of robotic, laparoscopic and open approaches in gastric cancer, comprising of information regarding surgical, clinical and oncological features. A chart review will be conducted to enter data of participants with gastric cancer, previously treated at the participating institutions. The database is the first of its kind, through an international electronic submission system and a HIPPA protected real time data repository from high volume gastric cancer centres.

Ethics and dissemination

This study is conducted in compliance with ethical principles originating from the Helsinki Declaration, within the guidelines of Good Clinical Practice and relevant laws/regulations. A multicentre study with a large number of patients will permit further investigation of the safety and efficacy as well as the long-term outcomes of robotic, laparoscopic and open approaches for the management of gastric cancer.

Trial registration number

NCT02325453; Pre-results.
Evaluation of genetic diversity among some commercial cultivars and Iranian wild strains of Agaricus bisporus by microsatellite markers
Authors: Rokni Nader , Goltapeh Ebrahim Mohammadi , Shafeinia Alireza , Safaie Naser
Published: October 2015

Agaricus bisporus (Lange) Imbach is the most widely cultivated mushroom in Iran. Lack of diversity in mushroom crops, especially where disease is concerned, creates a crucial risk for the currently grown cultivars. The aim of this study was to assess the genetic diversity among Iranian wild strains and some commercial cultivars by using microsatellite markers. Eighteen codominant microsatellite markers of A. bisporus (AbSSR) were used to distinguish 17 wild and commercial strains. All of the microsatellite markers used in this research gave clear banding patterns, and only one strain remained undistinguished. Among 106 generated alleles, the wild subgroup presented 53 alleles never found both in brown and white commercial cultivars, and 42 alleles never found in commercial brown strains. The dendrogram obtained by UPGMA clustering analysis separated A. bisporus strains into six groups. Based on our results, the high level of genetic diversity among Iranian wild strains, compared with the commercial strains, provides a new and promising source of diversity for A. bisporus breeding programs. To our knowledge this is the first relevant study of biodiversity in native Iranian populations of A. bisporus.
The punctuated seaward migration of Pacific lamprey (Entosphenus tridentatus): environmental cues and implications for streamflow management
Authors: Goodman Damon H. , Reid Stewart B. , Som Nicholas A. , Poytress William R.
Published: October 2015

We investigated emigration timing of juvenile Pacific lamprey (Entosphenus tridentatus) over a 10-year period in the Sacramento River, California, USA. Emigration was punctuated with 90% of macrophthalmia in daily catches of at least 50 individuals. Macrophthalmia were observed primarily between November and May, with among-year variation in median emigration date over four times that of sympatric anadromous salmon. Our best model associating catch and environmental factors included days from rain event, temperature, and streamflow. We found strong evidence for an association of catch with days from rain events, a surrogate for streamflow, with 93% of emigrants caught during an event and the two subsequent days. Emigration was more likely during nighttime during subdaily sampling after accounting for the effects of factors significantly associated with daily catch. These results emphasize the importance of natural variation in streamflow regimes and provide insight for management practices that would benefit emigrating lampreys, such as synchronizing dam releases with winter and spring storms to reduce migration time, timing diversions to avoid entrainment during emigration windows, and ensuring streamflows are sufficient to reach the ocean, thereby avoiding mass stranding events.
Birch and conifer deadwood favour early establishment and shade tolerance in yellow birch juveniles growing in sugar maple dominated stands
Authors: Lambert Jean-Bastien , Ameztegui Aitor , Delagrange Sylvain , Messier Christian
Published: October 2015

Small-seeded tree species such as yellow birch (YB, Betula alleghaniensis Britt.) require deadwood or mineral soil for their establishment. Although much research has been done comparing YB germination on leaf litter vs. exposed mineral soil, less is known about deadwood as a seedbed and how different seedbeds affect YB early growth along light availability and size gradients. We examine how three common seedbeds (deadwood, moss cover on deadwood, and mineral soil) affected establishment and growth, biomass partitioning, and morphological traits of YB juveniles growing in the understory of temperate mixed deciduous and coniferous forests in southern Quebec. A total of 274 YB were sampled in four sugar maple (Acer saccharum Marsh.) dominated northern hardwood stands where selective cuts had been applied 6 and 15 years prior to sampling. Over 75% of the YB found on deadwood were on material of birch and conifer origin, although these species made less than 40% of the basal area. YB juveniles growing on deadwood showed traits that improve survival in shade such as reduced height growth for tall plants, higher efficiency in resource capture, and multilayered crowns. Our results demonstrate the importance of deadwood of birch and conifer origin in maintaining an abundant, natural, spatially well-distributed, and multistoried regeneration of YB.
Implications of the first AMS-02 antiproton data for dark matter
Authors: Jin Hong-Bo , Wu Yue-Liang , Zhou Yu-Feng
Published: October 2015

The implications of the first AMS-02 [Formula: see text] data for the propagation of cosmic rays and the properties of dark matter (DM) are discussed. Using various diffusive re-acceleration (DR) propagation models, one can derive very conservative upper limits on the DM annihilation cross sections. The limits turned out to be compatible with that from the Fermi-LAT gamma-ray data on the dwarf spheroidal satellite galaxies. The flattening of the [Formula: see text] spectrum above [Formula: see text] 100 GeV in the current data still leaves some room for TeV scale DM particles. More antiproton data at high kinetic energies are needed to constrain the properties of the DM particles.