bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Cyclic GMP Export by Multidrug Resistance Protein 4: A New Strategy to Treat Erectile Dysfunction?
Authors: Boydens Charlotte , Pauwels Bart , Vanden Daele Laura , Van de Voorde Johan 
Published: March 2017

Abstract

Background
Intracellular cyclic guanosine monophosphate (cGMP) concentrations are regulated by degradation enzymes (phosphodiesterases) and by active transport across the plasma membrane by multidrug resistance proteins (MRPs) 4 and 5.

Aim
To evaluate the functional effect of MRP-4 inhibition and the role of MRP-4–mediated cGMP export in mouse corpora cavernosa.

Methods
Isometric tension of mouse corpora cavernosa was measured after cumulative addition of MK-571, an inhibitor of MRP-4, or sildenafil, a phosphodiesterase type 5 inhibitor. In addition, the effect of MRP-4 inhibition on cGMP-independent and cGMP-dependent relaxations was studied. In vivo intracavernosal pressure and mean arterial pressure measurements were performed after intracavernosal injection of MK-571. The effect of MRP-4 inhibition on cGMP content was determined using an enzyme immunoassay kit.

Outcomes
Measurement of the effect of MK-571 on cGMP content, relaxant responses of mouse corpora cavernosa to cGMP-independent and cGMP-dependent vasodilating substances, and determination of the ratio of intracavernosal pressure to mean arterial pressure after intracavernosal injection of MK-571.

Results
MK-571 and sildenafil relaxed the corpora cavernosa concentration dependently, with sildenafil being the more potent relaxing compound. Furthermore, MK-571 enhanced relaxing responses to cGMP-dependent substances, such as sodium nitroprusside, sildenafil, acetylcholine, and electrical field stimulation, with the latter even under in vitro diabetic conditions. In contrast, cGMP-independent relaxations were not altered by MRP-4 inhibition. Intracavernosal administration of MK-571 significantly increased intracavernosal pressure, with minimal effect on mean arterial pressure. The cGMP analysis showed that MRP-4 inhibition was accompanied by increased cGMP levels.

Clinical Translation
MRP-4, at least when targeted locally in the penis or when combined with a phosphodiesterase type 5 inhibitor, might be a valuable alternative strategy for the treatment of (diabetic) erectile dysfunction.

Strengths and Limitations
This study is the first to demonstrate an in vitro direct relaxant and an in vivo pro-erectile effect of the MRP-4 inhibitor, MK-571, on mouse corpora cavernosa. However, the functional effect of MRP-5–mediated export in mouse corpora cavernosa was not explored, which has been suggested to play the predominant role in cGMP export.

Conclusion
Inhibition of MRP-4 increases basal and stimulated levels of cGMP, leading to corpora cavernosa relaxation and penile erection. Therefore, in addition to degradation of cGMP, export of cGMP by MRP-4 could contribute substantially to regulating cGMP levels in mouse corpora cavernosa.
Gain of regularity for equations of KdV type
Authors: Craig W. , Kappeler T. , Strauss W. 
Published: March 2017

This article discusses questions of the smoothness of solutions to nonlinear dispersive evolution equations. We consider equations of KdV type, that is, of the general form

∂_{t}u + f\left(∂_{x}^{3}u,∂_{x}^{2}u,∂_{x}u,u;\:x,t\right) = 0

with

x\in \mathbf R

. The hypothesis on the nonlinear function

f

is principally that

∂_{∂_{x}^{3}u}f≧\mathrm{C}≧0

, so that dispersive effects are dominant. We show that if the function

u(0, x)

decays faster than polynomially on

\mathbf R^+

, and possesses certain minimal regularity, then
a priori
the solution

u(t, x) \in C^∞

for

t > 0

. Furthermore, the relationship between the rate of decay and the amount of gain of regularity is quantified; if

\int _{−\mathrm{∞}}^{\mathrm{∞}}u^{2}\left(0,x\right)\:\left(1 + \left|x_{ + }\right|^{k}\right)\:dx < \mathrm{∞}

then

u\left(t,\:.\right) \in \mathrm{H}_{\mathrm{loc}}^{k}\left(\mathbf{R}\right)

for all

0 < t ≦T

, and

u\left(t,x\right) \in \mathrm{L}^{1}\left(\left[0,\mathrm{T}\right];\mathrm{H}_{\mathrm{loc}}^{k + 1}\left(\mathbf{R}\right)\right)

where

T

is the existence time.

Résumé
Cet article démontre certaines propriétés de régularité des solutions des équations d’évolution dispersives non linéaires. Nous considérons les équations du type KdV, de la forme

∂_{t}u + f\left(∂_{x}^{3}u,∂_{x}^{2}u,∂_{x}u,u;\:x,t\right) = 0

où

x\in \mathbf R

. L’hypothèse la plus importante sur la fonction

f

est que

∂_{∂_{x}^{3}u}f≧\mathrm{C} > 0

, pour que les effets dispersifs soient dominants. Nous montrons que, si la fonction

u(0, x)

décroît vers zéro plus vite que les polynomes sur

\mathbf R^+

, et si elle est de minimale régularité,
a priori
la solution

u(t, x) \in C^∞

pour

t > 0

. En plus, la relation entre la vitesse de décroissance et l’ordre de régularité supplémentaire est quantifiée; si

\int _{−\mathrm{∞}}^{\mathrm{∞}}u^{2}\left(0,x\right)\left(1 + \left|x_{ + }\right|^{k}\right)dx < \mathrm{∞}

alors

u\left(t,\:.\right) \in \mathrm{H}_{\mathrm{loc}}^{k}\left(\mathbf{R}\right)

pour tout

0<t≦T

, et

u\left(t,x\right) \in \mathrm{L}^{1}\left(\left[0,\mathrm{T}\right];\mathrm{H}_{\mathrm{loc}}^{k + 1}\left(\mathbf{R}\right)\right)

où

T

est le temps d’existence.
Closed orbits of fixed energy for a class of $N$-body problems
Authors: Coti-Zelati V. , Ambrosetti A. 
Published: March 2017

We prove the existence of periodic solutions with prescribed energy for a class of

N

-body type problems.

Résumé

Nous démontrons l’existence de solutions périodiques à énergie fixée pour une classe de problèmes de type

N

-corps.
Concentration of solutions to elliptic equations with critical nonlinearity
Authors: Rey O. 
Published: March 2017

We study the asymptotic behavior as

ε

goes to zero of solutions in

\mathrm{H}_{0}^{1}\left(\mathrm{\Omega }\right)

to the equation:

−Δu = \left|u\right|^{4/ \left(\mathrm{N}−2\right)}u + \mathrm{\varepsilon }\:f\left(x\right)

, where

Ω

is a bounded domain in

\mathbf R^N

. We show the existence of solutions to the problem which blow-up at some well-defined points, depending on

f

, for

ε = 0

.

Résumé

Nous étudions le comportement asymptotique quand ε tend vers zèro de solutions dans

\mathrm{H}_{0}^{1}\left(\mathrm{\Omega }\right)

de l'équation :

−Δu = \left|u\right|^{4/ \left(\mathrm{N}−2\right)}u + \mathrm{\varepsilon }\:f\left(x\right),

où

Ω

est un ouvert borné de

\mathbf R^N

. Nous montrons l’existence de solutions du problème qui explosent en des points caractérisés précisément en fonction de

f

, pour

ε = 0

.
Minimal interface criterion for phase transitions in mixtures of Cahn–Hilliard fluids
Authors: Baldo Sisto 
Published: March 2017

In this paper we extend the Van der Waals–Cahn–Hilliard theory of phase transitions to the case of a mixture of

n

non-interacting fluids. By describing the state of the mixture as given by a vector density function

u = (u_1, …, u_n)

, the problem consists in studying the asymptotic behaviour as

\mathrm{\varepsilon }\rightarrow 0^{ + }

of minimizers of the energy functionals:

\mathrm{E}_{\mathrm{\varepsilon }}\left(u\right) = \int _{\mathrm{\Omega }}|\mathrm{\varepsilon }^{2}|\mathrm{D}u|^{2} + \mathrm{W}(u)|\mathrm{dx}

under the volume constraint

\int _{\mathrm{\Omega }}u(x)\:dx = m

, with

m\in \mathbf R^n

fixed. The function

W

, which represents the Gibbs free energy, is non-negative and vanishes only in a finite number of points

α_1, …, α_k\in \mathbf R^n

. The result is that the minimizers asymptotically approach a configuration which corresponds to a partition of the container

Ω

into

k

subsets whose boundaries satisfy a minimality condition.

Résumé

Dans cet article nous étendons la théorie des transitions de phase de Van der Waals–Cahn–Hilliard au cas d’un mélange de

n

fluides non intérageants. En supposant l’état du mélange décrit par une fonction vectorielle de densité

u = (u_1, …, u_n)

, le problème consistera dans l’étude du comportement asymptotique par

\mathrm{\varepsilon }\rightarrow 0^{ + }

des minimisants des énergies :

\mathrm{E}_{\mathrm{\varepsilon }}\left(u\right) = \int _{\mathrm{\Omega }}|\mathrm{\varepsilon }^{2}|\mathrm{D}u|^{2} + \mathrm{W}(u)|\mathrm{dx}

sous la contrainte de volume

\int _{\mathrm{\Omega }}u(x)\:dx = m

, avec

m\in \mathbf R^n

fixé. La fonction W représente l’énergie libre de Gibbs, à valeurs non négatives et qui est nulle sur un nombre fini de points

α_1, …, α_k \in \mathbf R^n

. Nous obtenons alors que les minimisants approchent asymptotiquement une configuration qui corresponds à une partition du container

Ω

en

k

sous-ensembles dont les bords satisfont à une certaine condition de minimalité.
On a classical problem of the calculus of variations without convexity assumptions
Authors: Cellina A. , Colombo G. 
Published: March 2017

We show that the functional

\mathrm{I}(x) = \int _{0}^{\mathrm{T}}g(t,x(t))\:dt + \int _{0}^{\mathrm{T}}h(t,x′(\mathrm{t}))\:dt

attains a minimum under the condition that

g

be concave in

x

.

Résumé
Nous montrons que le fonctionnel

\mathrm{I}(x) = \int _{0}^{\mathrm{T}}g(t,x(t))\:dt + \int _{0}^{\mathrm{T}}h(t,x′(\mathrm{t}))\:dt

atteint le minimum sous la condition de concavité sur

g

.
On the density of the range for some nonlinear operators
Authors: Long Yiming 
Published: March 2017

We study the existence of periodic solutions for a class of nonlinear Hamiltonian systems

\dot z -\mathscr J H'(z)=f(t).

By using the Leray–Schauder Theorem to solve a modified problem and passing to a limit, we show that

\mathscr J d/td -\mathscr J H'(.)

has a dense range in

\mathscr L^2

. We also obtain similar density results for nonlinear Schrödinger operators and other problems.

Résumé
Nous étudions l’existence de solutions périodiques pour une classe de systèmes Hamiltoniens non linéaires

\dot z -\mathscr J H'(z)=f(t).

A l’aide du théorème de Leray–Schauder nous résolvons un problème modifié et passons à la limite. On montre que l’opérateur

\mathscr J d/td -\mathscr J H'(.)

a une image dense dans

\mathscr L^2

. Nous obtenons aussi des résultats semblables pour d’autres opérateurs dont les opérateurs de Schrödinger non linéaires.
The global Cauchy problem for the non linear Klein-Gordon equation-II
Authors: Ginibre J. , Velo G. 
Published: March 2017

We study the Cauchy problem for a class of non linear Klein–Gordon equations of the type

\"{\mathrm{\varphi }}−Δ\mathrm{\varphi } + f(\mathrm{\varphi }) = 0

by a contraction method. We prove the existence and uniqueness of strongly continuous global solutions in the energy space

H^1(ℝ^n)\oplus L^2(ℝ^n)

for arbitrary space dimension

n

under assumptions on

f

that cover the case of a sum of powers

λ|φ|^{p −1} φ

with

1≦p < 1+4/(n−2)

,

n≧2

and

λ >0

for the highest

p

. This provides an alternative proof of existence and uniqueness to that presented in a previous paper [7]. Some of the results can be extended to the critical case

p = 1+4/(n−2)

.

Résumé

On étudie le problème de Cauchy pour une classe d’équations de Klein–Gordon non linéaires du type

\"{\mathrm{\varphi }}−Δ\mathrm{\varphi } + f(\mathrm{\varphi }) = 0

par une méthode de contraction. On prouve l’existence et l’unicité de solutions méthode de contraction. On prouve l’existence et l’unicité de solutions gobales fortement continues dans l’espace d’énergie

H^1(ℝ^n)\oplus L^2(ℝ^n)

pour une dimension d’espace

n

quelconque, avec des hypothèses sur

f

qui couvrent le cas d’une somme de puissances

λ|φ|^{p −1} φ

avec

1≦p < 1+4/(n−2)

,

n≧2

et

λ > 0

pour la valeur de

p

la plus élevée. On obtient ainsi une démonstration de l’existence et de l’unicité différente de celle donnée dans un article précédent [7]. Une partie des résultats s’étend au cas critique

p = 1+4/(n−2)

.
Isotropic singularities of solutions of nonlinear elliptic inequalities
Authors: Richard Yves , Veron Laurent 
Published: March 2017

If

g

is nondecreasing function satisfying the weak singularities existence condition then all the positive solutions of

Δu ⩽ g(u) + f

in

B_1(0)\setminus \{0\}

where

f

is radial and integrable in

B_1(0)

are isotropic in measure near

0

. We apply this result to solutions of

Δu ± g(u) = 0

in particular when

g(r) \sim r|r|^{q − 1}

,

g(r) \sim e^{β r}

, or

g(r) = r(\mathrm{L}_{n}^{ + }r)^{\alpha }

.

Résumé

Si

g

est une fonction croissante sur

ℝ

vérifiant la condition d’existence de singularités faibles et

f

une fonction intégrable radiale dans

B_1(0)

, alors toutes les solutions positives de

Δu ⩽ g(u) + f

dans

B_1(0)\setminus \{0\}

sont isotropes en mesure près de

0

. Nous appliquons ce résultat aux solutions de

Δu ± g(u) = 0

, en particulier quand

g(r) \sim r|r|^{q − 1}

,

g(r) \sim e^{βr}

ou

g(r) = r(\mathrm{L}_{n}^{ + }r)^{\alpha}

.
Vitamin D deficiency and sufficiency among Canadian children residing at high latitude following the revision of the RDA of vitamin D intake in 2010
Authors: Munasinghe Lalani L. , Yuan Yan , Willows Noreen D. , Faught Erin L. , Ekwaru John P. , Veugelers Paul J. 
Published: March 2017

AbstractRecently, countries at high latitudes have updated their vitamin D recommendations to ensure adequate intake for the musculoskeletal health of their respective populations. In 2010, the dietary guidelines for vitamin D for Canadians and Americans aged 1–70 years increased from 5 μg/d to 15 μg/d, whereas in 2016 for citizens of the UK aged ≥4 years 10 μg/d is recommended. The vitamin D status of Canadian children following the revised dietary guidelines is unknown. Therefore, this study aimed to assess the prevalence and determinants of vitamin D deficiency and sufficiency among Canadian children. For this study, we assumed serum 25-hydroxy vitamin D (25(OH)D) concentrations <30 nmol/l as ‘deficient’ and ≥50nmol/l as ‘sufficient’. Data from children aged 3–18 years (n 2270) who participated in the 2012/2013 Canadian Health Measures Survey were analysed. Of all children, 5·6 % were vitamin D deficient and 71 % were vitamin D sufficient. Children who consumed vitamin D-fortified milk daily (77 %) were more likely to be sufficient than those who consumed it less frequently (OR 2·7; 95 % CI 1·4, 5·0). The 9 % of children who reported taking vitamin D-containing supplements in the previous month had higher 25(OH)D concentrations (OR 6·9 nmol/l; 95 % CI 1·1, 12·7 nmol/l) relative to those who did not. Children who were older, obese, of non-white ethnicity and from low-income households were less likely to be vitamin D sufficient. To improve vitamin D status, consumption of vitamin D-rich foods should be promoted, and fortification of more food items or formal recommendations for vitamin D supplementation should be considered.
Transnationalism as interdiscursivity: Korean managers of multinational corporations talking about mobility
Authors: Park Joseph Sung-Yul 
Published: March 2017

AbstractThis article explores how transnationalism can be understood as an interdiscursive process. By making connections with chronotopes of past places along a transmigrant's trajectory, interdiscursivity allows for the emergence of complex indexical meaning associated with different speakers and different ways of speaking, imbuing the transmigrant's mobility with specific social significance. This article demonstrates this point through an analysis of how South Korean mid-level managers of multinational corporations in Singapore imagined their positioning in the global workplace. By tracing the ways the managers employed metapragmatic discourse associated with multiple chronotopes to make sense of their reasonably successful but limited careers, it offers an account of how interdiscursivity shaped their understanding of their own positionality as Koreans working beyond the time-space of Korea. (Interdiscursivity, transnationalism, chronotope, Korea, English, intercultural communication)*
Metapragmatics of mobility
Authors: Lo Adrienne , Park Joseph 
Published: March 2017

AbstractThis introduction presents a framework for analyzing the semiotic dimensions of mobility. Drawing upon the notion of pathway (Wortham & Reyes 2015), it examines how mobility is facilitated by semiotic processes that link linguistic emblems with speaker images across time and space (Agha 2007). It focuses on the circulation of discursive forms, facilitated by media technologies and complex patterns of transnational interaction, which ascribe identities to people on the move and root such identities within hierarchical structures of the market on local, national, and transnational scales. Looking at how interdiscursive networks intersect with people's experience of mobility and the way they position themselves in social space, this article problematizes the divide between ‘micro’ and ‘macro’ approaches, offering a historically grounded approach to operations of power that permeate both metapragmatic discourse and experiences of mobility. (Mobility, metapragmatics, mediatization, interdiscursivity)*
Total chemical synthesis of a thermostable enzyme capable of polymerase chain reaction
Authors: Xu Weiliang , Jiang Wenjun , Wang Jiaxing , Yu Linping , Chen Ji , Liu Xianyu , Liu Lei , Zhu Ting F 
Published: March 2017

AbstractPolymerase chain reaction (PCR) has been a defining tool in modern biology. Towards realizing mirror-image PCR, we have designed and chemically synthesized a mutant version of the 352-residue thermostable Sulfolobus solfataricus P2 DNA polymerase IV with l-amino acids and tested its PCR activity biochemically. To the best of our knowledge, this enzyme is the largest chemically synthesized protein reported to date. We show that with optimization of PCR conditions, the fully synthetic polymerase is capable of amplifying template sequences of up to 1.5 kb. The establishment of this synthetic route for chemically synthesizing DNA polymerase IV is a stepping stone towards building a d-enzyme system for mirror-image PCR, which may open up an avenue for the creation of many mirror-image molecular tools such as mirror-image systematic evolution of ligands by exponential enrichment.
PNPLA1 is a transacylase essential for the generation of the skin barrier lipid ω-O-acylceramide
Authors: Ohno Yusuke , Kamiyama Nozomi , Nakamichi Shota , Kihara Akio 
Published: March 2017

AbstractLipids are the primary components of the skin permeability barrier, which is the body’s most powerful defensive mechanism against pathogens. Acylceramide (ω-O-acylceramide) is a specialized lipid essential for skin barrier formation. Here, we identify PNPLA1 as the long-sought gene involved in the final step of acylceramide synthesis, esterification of ω-hydroxyceramide with linoleic acid, by cell-based assays. We show that increasing triglyceride levels by overproduction of the diacylglycerol acyltransferase DGAT2 stimulates acylceramide production, suggesting that triglyceride may act as a linoleic acid donor. Indeed, the in vitro analyses confirm that PNPLA1 catalyses acylceramide synthesis using triglyceride as a substrate. Mutant forms of PNPLA1 found in patients with ichthyosis exhibit reduced or no enzyme activity in either cell-based or in vitro assays. Altogether, our results indicate that PNPLA1 is directly involved in acylceramide synthesis as a transacylase, and provide important insights into the molecular mechanisms of skin barrier formation and of ichthyosis pathogenesis.
Protectin DX increases survival in a mouse model of sepsis by ameliorating inflammation and modulating macrophage phenotype
Authors: Xia Haifa , Chen Lin , Liu Hong , Sun Zhipeng , Yang Wen , Yang Yiyi , Cui Shunan , Li Shengnan , Wang Yaxin , Song Limin , Abdelgawad Amro Fayez , Shang You , Yao Shanglong 
Published: March 2017

AbstractRecently, a serial of studies have demonstrated that lipid mediators derived from Omega-3 fatty acid docosahexaenoic acid have pro-resolving or anti-inflammatory effects in many inflammatory diseases. Here, we sought to evaluate whether Protectin DX (PDX, an isomer of Protecin D1), a newly identified lipid mediator, could protect mice against sepsis and explore the underling mechanism. Animal model of sepsis was established by cecum ligation and puncture (CLP). We found that PDX increased overall survival rate within eight days and attenuated multiple organ injury in septic mice. In addition, PDX reduced pro-inflammatory cytokines and bacterial load 24 h after CLP. Moreover, PDX promoted phagocytosis of peritoneal macrophages and increased the percentage of M2 macrophages in peritoneum of septic mice. In vitro, M2 macrophage markers (Arg1 and Ym1) and its transcriptional regulator (peroxisome proliferator-activated receptor-γ, PPAR-γ) were upregulated in Raw264.7 macrophages challenged with PDX. GW9662 (a PPAR-γ inhibitor) and PPAR-γ siRNA abrogated the induction of Arg1 and Ym1 by PDX in Raw264.7 cells. Taken together, our results suggest that PDX is able to promote M2 polarization, enhance phagocytosis activity of macrophage and accelerate resolution of inflammation, finally leading to increased survival rate of septic mice.
Methionine aminopeptidase 2 is a key regulator of apoptotic like cell death in Leishmania donovani
Authors: Kumar Ritesh , Tiwari Kartikeya , Dubey Vikash Kumar 
Published: March 2017

AbstractWe investigate the role of methionine aminopeptidase 2 (MAP2) in miltefosine induced programmed cell death (PCD) in promastigote form of L. donovani. We report that TNP-470, an inhibitor of MAP2, inhibits programmed cell death in miltefosine treated promastigotes. It inhibits the biochemical features of metazoan apoptosis, including caspase3/7 protease like activity, oligonucleosomal DNA fragmentation, collapse of mitochondrial transmembrane potential, and increase in cytosolic pool of calcium ions but did not prevent the cell death and phosphatidyl serine externalization. The data suggests that the MAP2 is involved in the regulation of PCD in parasite. Moreover, TNP-470 shows the leishmanicidal activity (IC50 = 15 µM) and in vitro inhibition of LdMAP2 activity (K
i
= 13.5 nM). Further studies on MAP2 and identification of death signaling pathways provide valuable information that could be exploited to understand the role of non caspase proteases in PCD of L. donovani.
Hybrid inorganic-organic capsules for efficient intracellular delivery of novel siRNAs against influenza A (H1N1) virus infection
Authors: Timin Alexander S. , Muslimov Albert R. , Petrova Aleksandra V. , Lepik Kirill V. , Okilova Maria V. , Vasin Andrey V. , Afanasyev Boris V. , Sukhorukov Gleb B. 
Published: March 2017

AbstractThe implementation of RNAi technology into the clinical practice has been significantly postponing due to the issues regarding to the delivery of naked siRNA predominantly to target cells. Here we report the approach to enhance the efficiency of siRNA delivery by encapsulating the siRNA into new carrier systems which are obtained via the combination of widely used layer-by-layer technique and in situ modification by sol-gel chemistry. We used three types of siRNAs (NP-717, NP-1155 and NP-1496) in encapsulated form as new therapeutic agents against H1N1 influenza virus infection. By employing the hybrid microcontainers for the siRNA encapsulation we demonstrate the reduction of viral nucleoprotein (NP) level and inhibition of influenza virus production in infected cell lines (MDCK and A549). The obtained hybrid carriers based on assembled biodegradable polyelectrolytes and sol-gel coating possess several advantages such as a high cell uptake efficiency, low toxicity, efficient intracellular delivery of siRNAs and the protection of siRNAs from premature degradation before reaching the target cells. These findings underpin a great potential of versatile microencapsulation technology for the development of anti-viral RNAi delivery systems against influenza virus infection.