bluuebunny/crossref_metadata_2025 huggingface dataset:
Commandeering the Ribosome: Lessons Learned from Dicistroviruses about Translation
Authors: Kerr Craig H. , Jan Eric
Published: April 2016

To replicate, all viruses depend entirely on the enslavement of host cell ribosomes for their own advantage. To this end, viruses have evolved a multitude of translational strategies to usurp the ribosome. RNA-based structures known as internal ribosome entry sites (IRESs) are among the most notable mechanisms employed by viruses to seize host ribosomes. In this article, we spotlight the intergenic region IRES from the
Dicistroviridae
family of viruses and its importance as a model for IRES-dependent translation and in understanding fundamental properties of translation.
Entry Sites of Venezuelan and Western Equine Encephalitis Viruses in the Mouse Central Nervous System following Peripheral Infection
Authors: Phillips Aaron T. , Rico Amber B. , Stauft Charles B. , Hammond Sean L. , Aboellail Tawfik A. , Tjalkens Ronald B. , Olson Ken E.
Published: April 2016

Venezuelan and western equine encephalitis viruses (VEEV and WEEV;
Alphavirus
;
Togaviridae
) are mosquito-borne pathogens causing central nervous system (CNS) disease in humans and equids. Adult CD-1 mice also develop CNS disease after infection with VEEV and WEEV. Adult CD-1 mice infected by the intranasal (i.n.) route, showed that VEEV and WEEV enter the brain through olfactory sensory neurons (OSNs). In this study, we injected the mouse footpad with recombinant WEEV (McMillan) or VEEV (subtype IC strain 3908) expressing firefly luciferase (fLUC) to simulate mosquito infection and examined alphavirus entry in the CNS. Luciferase expression served as a marker of infection detected as bioluminescence (BLM) by
in vivo
and
ex vivo
imaging. BLM imaging detected WEEV and VEEV at 12 h postinoculation (hpi) at the injection site (footpad) and as early as 72 hpi in the brain. BLM from WEEV.McM-fLUC and VEEV.3908-fLUC injections was initially detected in the brain's circumventricular organs (CVOs). No BLM activity was detected in the olfactory neuroepithelium or OSNs. Mice were also injected in the footpad with WEEV.McM expressing DsRed (
Discosoma
sp.) and imaged by confocal fluorescence microscopy. DsRed imaging supported our BLM findings by detecting WEEV in the CVOs prior to spreading along the neuronal axis to other brain regions. Taken together, these findings support our hypothesis that peripherally injected alphaviruses enter the CNS by hematogenous seeding of the CVOs followed by centripetal spread along the neuronal axis.

IMPORTANCE
VEEV and WEEV are mosquito-borne viruses causing sporadic epidemics in the Americas. Both viruses are associated with CNS disease in horses, humans, and mouse infection models. In this study, we injected VEEV or WEEV, engineered to express bioluminescent or fluorescent reporters (fLUC and DsRed, respectively), into the footpads of outbred CD-1 mice to simulate transmission by a mosquito. Reporter expression serves as detectable bioluminescent and fluorescent markers of VEEV and WEEV replication and infection. Bioluminescence imaging, histological examination, and confocal fluorescence microscopy were used to identify early entry sites of these alphaviruses in the CNS. We observed that specific areas of the brain (circumventricular organs [CVOs]) consistently showed the earliest signs of infection with VEEV and WEEV. Histological examination supported VEEV and WEEV entering the brain of mice at specific sites where the blood-brain barrier is naturally absent.
Drugs to treat obesity: do they work?
Authors: Kim Sarah
Published: April 2016

Obesity is a disease that has historically eluded effective medical therapy. Prior to 2012, phentermine and orlistat were the only medications available to treat obesity in the USA, with phentermine approved only for short-term use. However, as of 2015, the repertoire of pharmacological agents available to treat obesity has greatly expanded to include four new drugs: lorcaserin, phentermine/topiramate extended release (ER), naltrexone ER/wellbutrin ER and liraglutide. Each has a unique mechanism of action and all are intended for long-term use. These newer medications share a common strategy to promote weight loss in that they are designed to manipulate the control of hunger and satiety in the central nervous system. Interestingly, the majority of these new agents are combinations of older medications that have been used for conditions other than obesity. The amount of weight loss seen with these agents beyond placebo varies but generally falls in the range of 3–10% of starting weight and requires continual use of the drug in order for weight loss to be sustained. In addition, each drug has a unique side effect profile that should be carefully considered when selecting the best agent for a given individual. This article provides a review of these recently approved medications focusing on efficacy, side effect profiles and appropriate application to the individual patient.
Veterinary hospice and palliative care: a comprehensive review of the literature
Authors: Goldberg Katherine J.
Published: April 2016

The death of a pet is a universal experience for those who share their lives with animals. In parallel with a rising interest in palliative medicine, hospice care and advance‐care planning within human medicine, increasing attention is currently being given to serious illness and death within veterinary medicine. Our ability to prolong life has created the need for thoughtful end of life discourse. Interest in hospice and palliative care for companion animals is on the rise, yet there has been limited scholarly research in these areas to date. This review concludes that veterinary hospice and palliative care is currently hindered by an inadequate amount of scholarly research to guide clinicians. Given a lack of prospective studies in veterinary hospice and palliative care to date, a significant opportunity exists for veterinary teaching institutions to contribute to the literature in an important and growing field.
Reaching for the top
Authors: Mancinelli Elisabetta
Published: April 2016

Elisabetta Mancinelli is the first vet in Europe to embark on, and pass by examination, the European Diploma in Zoological Medicine with a specialty in small mammals. Having qualified in Italy, she came to the UK nine years ago to pursue further studies in exotic animal medicine
Optimality of continuous cover vs. clear-cut regimes in managing forest resources
Authors: Tahvonen Olli , Rämö Janne
Published: April 2016

Optimization models on continuous cover forestry are complicated and typically incompatible with rotation models. This dichotomy is theoretically unsatisfactory and makes the choice between clearcuts and continuous cover forestry vague. We present a theoretically sound and empirically detailed generalized setup with an optimal clear-cut regime (or even-aged management) and optimal continuous cover regime (or uneven-aged management) as special cases. It includes a size-structured growth model, variable and fixed harvesting costs, and allows for the completely flexible optimization of harvest timing in both regimes. Flexible harvest timing becomes essential when optimizing the transition from clear-cut regimes toward continuous cover forestry. The model is applied to Norway spruce (Picea abies (L.) Karst.) and solved as a dynamic mixed-integer problem. Low or moderate site productivity, an interest rate above 2%, and a high artificial regeneration cost support the optimality of continuous cover forestry. In its most general form, the optimal clear-cut regime does not exist when the continuous cover regime is globally optimal, and when it exists, the rotation period lengthens with interest rate. The optimal choice between forest management regimes may depend on the initial stand state and whether the naturally regenerated seedlings are utilized in solutions with clearcuts. Maximizing sustainable yield favors clearcuts.
Yarman’s approach predicts anomalous gravitational bending of high-energy gamma-quanta
Authors: Arik Metin , Yarman Tolga , Kholmetskii Alexander , Yarman Ozan
Published: April 2016

We predict anomalous gravitational bending of gamma rays using the gravitational framework of Yarman’s approach, abbreviated hereinafter as “YARK” from the initials of the co-authors to designate their teamwork. In contrast to the metric layout of the general theory of relativity (GTR), YARK theory is founded directly on the energy conservation law pertaining to interaction between masses. Despite the fact that predictions made respectively by GTR and YARK regarding cornerstone astrophysical observations appear remarkably identical to each other, the philosophies behind them are irreconcilably different. To test which theory comes closer to the reality, one should propose ways to distinguish their success at the experimental level. Note that bending of light in GTR represents a purely metric effect, which cannot depend on the energy of photons, whereas YARK conceptually allows the deflection of photons across a gravitational environment contingent upon either their wave-like or corpuscular-like behavior. In the case of “wave-like propagation”, which we deem particular to low-energy photons (including the visible range), YARK arrives at the same results as GTR; whereas for high-energy gamma-quanta, which we deem to signify “corpuscular-like propagation”, the deflection in a gravitational field practically vanishes in YARK. Given this opportunity to test YARK theory against GTR, we discuss possible experimental setups relevant to the subject.
Evaluation of forest management effects on the mineral soil carbon pool of a lowland, mixed-species forest in Maine, USA
Authors: Puhlick Joshua J. , Fernandez Ivan J. , Weiskittel Aaron R.
Published: April 2016

Concerns about climate change have increased interest in ways to maximize carbon (C) storage in forests through the use of alternative forest management strategies. However, the influence of these strategies on soil C pools is unclear. The primary objective of this study was to test for differences in mineral soil C stocks among various silvicultural and harvesting treatments that were initiated in the 1950s and have been maintained since on the Penobscot Experimental Forest in central Maine, USA. Five mineral soil cores below the surface organic horizon to a depth of 1 m were collected from each replicate (n = 2) of selection, shelterwood, and commercial clearcut treatments. For these treatments, the mean mineral soil C stock was 47.7 ± 16.4 Mg ha−1 (mean ± SD). We found no significant differences in average mineral soil C stocks among treatments. However, a post hoc power analysis indicated that the probability of detecting a significant treatment effect was only 6%. We determined that 98 stands per treatment would be required to be 80% certain that the F test would detect a difference in average mineral soil C stocks whenever any pair of treatments had C stocks differing by more than 5 Mg ha−1.
Multi-Biosignal Analysis for Epileptic Seizure Monitoring
Authors: Cogan Diana , Birjandtalab Javad , Nourani Mehrdad , Harvey Jay , Nagaraddi Venkatesh
Published: April 2016

Persons who suffer from intractable seizures are safer if attended when seizures strike. Consequently, there is a need for wearable devices capable of detecting both convulsive and nonconvulsive seizures in everyday life. We have developed a three-stage seizure detection methodology based on 339 h of data (26 seizures) collected from 10 patients in an epilepsy monitoring unit. Our intent is to develop a wearable system that will detect seizures, alert a caregiver and record the time of seizure in an electronic diary for the patient’s physician. Stage I looks for concurrent activity in heart rate, arterial oxygenation and electrodermal activity, all of which can be monitored by a wrist-worn device and which in combination produce a very low false positive rate. Stage II looks for a specific pattern created by these three biosignals. For the patients whose seizures cannot be detected by Stage II, Stage III detects seizures using limited-channel electroencephalogram (EEG) monitoring with at most three electrodes. Out of 10 patients, Stage I recognized all 11 seizures from seven patients, Stage II detected all 10 seizures from six patients and Stage III detected all of the seizures of two out of the three patients it analyzed.
Examining a covariant and renormalizable quantum field theory in de Sitter space by studying “black hole radiation”
Authors: Pejhan Hamed , Rahbardehghan Surena
Published: April 2016

Respecting that any consistent quantum field theory in curved space–time must include black hole radiation, in this paper, we examine the Krein–Gupta–Bleuler (KGB) formalism as an inevitable quantization scheme in order to follow the guideline of the covariance of minimally coupled massless scalar field and linear gravity on de Sitter (dS) background in the sense of Wightman–Gärding approach, by investigating thermodynamical aspects of black holes. The formalism is interestingly free of pathological large distance behavior. In this construction, also, no infinite term appears in the calculation of expectation values of the energy–momentum tensor (we have an automatic and covariant renormalization) which results in the vacuum energy of the free field to vanish. However, the existence of an effective potential barrier, intrinsically created by black holes gravitational field, gives a Casimir-type contribution to the vacuum expectation value of the energy–momentum tensor. On this basis, by evaluating the Casimir energy–momentum tensor for a conformally coupled massless scalar field in the vicinity of a nonrotating black hole event horizon through the KGB quantization, in this work, we explicitly prove that the hole produces black-body radiation which its temperature exactly coincides with the result obtained by Hawking for black hole radiation.
Superfield Hamiltonian quantization in terms of quantum antibrackets
Authors: Batalin Igor A. , Lavrov Peter M.
Published: April 2016

We develop a new version of the superfield Hamiltonian quantization. The main new feature is that the BRST-BFV charge and the gauge fixing Fermion are introduced on equal footing within the sigma model approach, which provides for the actual use of the quantum/derived antibrackets. We study in detail the generating equations for the quantum antibrackets and their primed counterparts. We discuss the finite quantum anticanonical transformations generated by the quantum antibracket.
Thermodynamics of the d-wave pairing in organic superconductors
Authors: Kruchinin S. , Zolotovsky A. , Yamashita S. , Nakazawa Y.
Published: April 2016

Organic superconductors with [Formula: see text]-type structure are most frequently identified as nodal gap superconductors from the experimental observation of a power-law behavior in the low-temperature thermodynamic properties such as specific heat capacity. We perform series of theoretical calculations of specific heat capacity of three typical organic complexes with different transition temperatures by using Bogolyubov–de Gennes equations. The good agreement between the experimental data and the calculations demonstrates that the [Formula: see text]-wave pairing is certainly realized in these superconductors.
An analytical solution for the graphene electronic spectrum in the presence of external fields and confinement potential
Authors: Çağatay Bengü , Bilge Ocak S.
Published: April 2016

An algebraic solution of [Formula: see text]-dimensional Dirac equation describing the massless Dirac fermions in the presence of both magnetic field perpendicular to the graphene plane and in-plane homogeneous electric field together with a quadratic confinement potential is investigated. The associated energy eigenvalues are obtained within the framework of unitary transformation scheme. It is shown that the decreasing quadratic confinement potential strength leads to the enhancement of the Landau levels.
Non-triviality of some one-relator products of three groups
Authors: Chinyere Ihechukwu , Howie James
Published: April 2016

In this paper we study a group [Formula: see text] which is the quotient of a free product of three nontrivial groups by the normal closure of a single element. In particular, we show that if the relator has length at most eight, then [Formula: see text] is nontrivial. In the case where the factors are cyclic, we prove the stronger result that at least one of the factors embeds in [Formula: see text].
Nullification numbers of knots with up to 10 crossings
Authors: Ernst Claus , Montemayor Anthony
Published: April 2016

In this paper, we consider the nullification numbers [Formula: see text] of the 249 prime knots up to 10 crossings to an unlink with [Formula: see text] components. This extends an existing table of knot nullification numbers up to nine crossings in [C. Ernst, A. Montemayor and A. Stasiak, Nullification of small knots, Prog. Theor. Phys. Suppl. 191 (2011) 66–77].
THE EFFECT OF FREEZING ON BIOMECHANICAL PROPERTIES OF THE CARPAL TUNNEL SUBSYNOVIAL CONNECTIVE TISSUE
Authors: Filius Anika , Thoreson Andrew , Dharan Abhishek , Mara Kristin , An Kai-Nan , Zhao Chunfeng , Amadio Peter C.
Published: April 2016

Biomechanical evaluation of the subsynovial connective tissue (SSCT) provides insight into the causes of carpal tunnel syndrome. Studies of carpal tunnel mechanics have been performed using fresh-frozen cadaver tissue. Freezing can affect mechanical properties of some tissues, but its effect on SSCT is unknown. A total of 16 rabbit paws were harvested from eight New Zealand rabbits and subjected to mechanical testing consisting of three repeated tendon excursions in sets of three different excursion magnitudes. One paw from each animal was unfrozen. The contralateral paw was frozen and thawed before testing. Force, energy and stiffness of the first cycle of each set were evaluated, as were ratios of the second to first cycle for each parameter. Two-factor ANOVA with repeated measures over both factors was performed. No significant interactions between factors were found. There were no significant differences between fresh and frozen paws for any parameters, though there were significant differences between excursion amplitudes. The damage threshold was not different between fresh and frozen paws. This study demonstrated that freezing rabbit subsynovial connective tissue does not significantly change its mechanical properties. The same may be true for human cadaver tissues. Results of cadaver mechanical testing may not be influenced by this preservation technique.
Hankel ideals of 2-minors associated with pairs of proper intervals graphs
Authors: Chaudhry Faryal , Qureshi Ayesha Asloob
Published: April 2016

We study ideals generated by [Formula: see text]-minors of generic Hankel matrices.
PERISTALTIC FLOW AND HYDRODYNAMIC DISPERSION OF A REACTIVE MICROPOLAR FLUID-SIMULATION OF CHEMICAL EFFECTS IN THE DIGESTIVE PROCESS
Authors: RAVI KIRAN G. , RADHAKRISHNAMACHARYA G. , BÉG O. ANWAR
Published: April 2016

The hydrodynamic dispersion of a solute in peristaltic flow of a reactive incompressible micropolar biofluid is studied as a model of chyme transport in the human intestinal system with wall effects. The long wavelength approximation, Taylor's limiting condition and dynamic boundary conditions at the flexible walls are used to obtain the average effective dispersion coefficient in the presence of combined homogeneous and heterogeneous chemical reactions. The effects of various pertinent parameters on the effective dispersion coefficient are discussed. It is observed that average effective dispersion coefficient increases with amplitude ratio which implies that dispersion is enhanced in the presence of peristalsis. Furthermore, average effective dispersion coefficient is also elevated with the micropolar rheological and wall parameters. Conversely dispersion is found to decrease with cross viscosity coefficient, homogeneous and heterogeneous chemical reaction rates. The present simulations provide an important benchmark for future chemo-fluid-structure interaction (FSI) computational models.
How big is big? Separation by conventional methods, X-ray and electronic structures of positional isomers of bis-tert-butylisocyano adduct of 2(3),9(10),16(17),23(24)-tetrachloro-3(2),10(9),17(16),24(23)-tetra(2,6-di-iso-propylphenoxy)-phthalocyaninato iron(II) complex
Authors: Anderson Derrick R. , Solntsev Pavlo V. , Rhoda Hannah M. , Nemykin Victor N.
Published: April 2016

A presence of bulky 2,6-di-iso-propylphenoxy groups in bis-tert-butylisocyano adduct of 2(3),9(10),16(17),23(24)-tetrachloro-3(2),10(9),17(16),24(23)-tetra(2,6-di-iso-propylphenoxy)-phthalocyaninato iron(II) complex allows separation of two individual positional isomers and a mixture of the remaining two isomers using conventional chromatography. X-ray structures of “[Formula: see text]” and “[Formula: see text]” isomers were confimed by X-ray crystallography. Density functional theory (DFT) and time-dependent DFT (TDDFT) calculations of each individual positional isomer allowed insight into their electronic structures and vertical excitation energies, which were correlated with the experimental UV-vis and MCD spectra.
Max Euwe's Set-Theoretic Observations on the Game of Chess — Introductory Notes
Authors: Vela Velupillai K.
Published: April 2016

This is a brief introduction to the Classic on Constructive Game Theory by Max Euwe (18), translated and republished in this issue of New Mathematics and Natural Computation. The task and aim of the Introduction is simply to provide a context, and some historical notes, particularly on the difference between Brouwer's approach to Set Theory — an Intuitionistic-Constructive approach and that of Zermelo.
On primitive covering numbers
Authors: Jones Lenny , White Daniel
Published: April 2016

In 2007, Zhi-Wei Sun defined a covering number to be a positive integer [Formula: see text] such that there exists a covering system of the integers where the moduli are distinct divisors of [Formula: see text] greater than 1. A covering number [Formula: see text] is called primitive if no proper divisor of [Formula: see text] is a covering number. Sun constructed an infinite set [Formula: see text] of primitive covering numbers, and he conjectured that every primitive covering number must satisfy a certain condition. In this paper, for a given [Formula: see text], we derive a formula that gives the exact number of coverings that have [Formula: see text] as the least common multiple of the set [Formula: see text] of moduli, under certain restrictions on [Formula: see text]. Additionally, we disprove Sun’s conjecture by constructing an infinite set of primitive covering numbers that do not satisfy his primitive covering number condition.
On the average distribution of divisors of friable numbers
Authors: Drappeau Sary
Published: April 2016

A number is said to be [Formula: see text]-friable if it has no prime factor greater than [Formula: see text]. In this paper, we prove a central limit theorem on average for the distribution of divisors of [Formula: see text]-friable numbers less than [Formula: see text], for all [Formula: see text] satisfying [Formula: see text]. This was previously known under the additional constraint [Formula: see text], by work of Basquin. Our argument relies on the two-variable saddle-point method.
Finding special factors of values of polynomials at integer points
Authors: Badziahin Dmitry
Published: April 2016

We investigate the divisors [Formula: see text] of the numbers [Formula: see text] for various polynomials [Formula: see text] such that [Formula: see text]. We obtain the complete classification of such divisors for a class of polynomials, in particular for [Formula: see text]. We also construct a fast algorithm which provides all such factorizations up to a given limit for another class, for example for [Formula: see text]. We use these results to find all the divisors [Formula: see text] of numbers [Formula: see text] and [Formula: see text]. For the numbers [Formula: see text] the complete classification of such divisors is provided while for the numbers [Formula: see text] the given classification is proved to be exhaustive only for [Formula: see text].
Multiplicative Zagreb indices of cacti
Authors: Wang Shaohui , Wei Bing
Published: April 2016

Let [Formula: see text] be multiplicative Zagreb index of a graph [Formula: see text]. A connected graph is a cactus graph if and only if any two of its cycles have at most one vertex in common, which is a generalization of trees and has been the interest of researchers in the field of material chemistry and graph theory. In this paper, we use a new tool to obtain the upper and lower bounds of [Formula: see text] for all cactus graphs and characterize the corresponding extremal graphs.
Growth of layer-bound normal faults under a regional anisotropic stress field
Authors: Ghalayini R. , Homberg C. , Daniel J. M. , Nader F. H.
Published: April 2016

Layer-bound normal faults commonly form polygonal faults with fine-grained sediments early in their burial history. When subject to anisotropic stress conditions, these faults will be preferentially oriented. In this study we investigate how faults grow, evolve and interact within regional-scale layer-bound fault systems characterized by parallel faults. The intention is to understand the geometry and growth of faults by applying qualitative and quantitative fault analysis techniques to a 3D seismic reflection dataset from the Levant Basin, an area containing a unique layer-bound normal fault array. This analysis indicates that the faults were affected by mechanical stratigraphy, causing preferential nucleation sites of fault segments, which were later linked. Our interpretation suggests that growth of layer-bound faults at a basin scale generally follows the isolated model, accumulating length proportional to displacement and, when subject to an anisotropic regional stress field, resembling to a great extent classical tectonic normal faults.
Bayesian Combinatorial Auctions
Authors: Christodoulou George , Kovács Annamária , Schapira Michael
Published: April 2016

We study the following simple Bayesian auction setting:
m
items are sold to
n
selfish bidders in
m
independent second-price auctions. Each bidder has a
private
valuation function that specifies his or her complex preferences over
all
subsets of items. Bidders only have
beliefs
about the valuation functions of the other bidders, in the form of probability distributions. The objective is to allocate the items to the bidders in a way that provides a good approximation to the optimal social welfare value. We show that if bidders have submodular or, more generally, fractionally subadditive (aka XOS) valuation functions, every Bayes-Nash equilibrium of the resulting game provides a 2-approximation to the optimal social welfare. Moreover, we show that in the full-information game, a pure Nash always exists and can be found in time that is polynomial in both
m
and
n
.
Declarative Cleaning of Inconsistencies in Information Extraction
Authors: Fagin Ronald , Kimelfeld Benny , Reiss Frederick , Vansummeren Stijn
Published: April 2016

The population of a predefined relational schema from textual content, commonly known as Information Extraction (IE), is a pervasive task in contemporary computational challenges associated with Big Data. Since the textual content varies widely in nature and structure (from machine logs to informal natural language), it is notoriously difficult to write IE programs that unambiguously extract the sought information. For example, during extraction, an IE program could annotate a substring as both an address and a person name. When this happens, the extracted information is said to be
inconsistent
, and some way of removing inconsistencies is crucial to compute the final output. Industrial-strength IE systems like GATE and IBM SystemT therefore provide a built-in collection of
cleaning
operations to remove inconsistencies from extracted relations. These operations, however, are collected in an ad hoc fashion through use cases. Ideally, we would like to allow IE developers to declare their own policies. But existing cleaning operations are defined in an algorithmic way, and hence it is not clear how to extend the built-in operations without requiring low-level coding of internal or external functions.

We embark on the establishment of a framework for declarative cleaning of inconsistencies in IE through principles of database theory. Specifically, building upon the formalism of
document spanners
for IE, we adopt the concept of
prioritized repairs
, which has been recently proposed as an extension of the traditional database repairs to incorporate priorities among conflicting facts. We show that our framework captures the popular cleaning policies, as well as the POSIX semantics for extraction through regular expressions. We explore the problem of determining whether a cleaning declaration is unambiguous (i.e., always results in a single repair) and whether it increases the expressive power of the extraction language. We give both positive and negative results, some of which are general and some of which apply to policies used in practice.
Drowning in triangle soup: the quest for a better 3-D printing file format
Authors: Louis-Rosenberg Jesse
Published: April 2016

File formats for additive manufacturing are lagging behind the capabilities of 3-D printing technology itself, and no one is doing anything about it.
Methods for the Analysis of Protein Phosphorylation–Mediated Cellular Signaling Networks
Authors: White Forest M. , Wolf-Yadlin Alejandro
Published: April 2016

Protein phosphorylation–mediated cellular signaling networks regulate almost all aspects of cell biology, including the responses to cellular stimulation and environmental alterations. These networks are highly complex and comprise hundreds of proteins and potentially thousands of phosphorylation sites. Multiple analytical methods have been developed over the past several decades to identify proteins and protein phosphorylation sites regulating cellular signaling, and to quantify the dynamic response of these sites to different cellular stimulation. Here we provide an overview of these methods, including the fundamental principles governing each method, their relative strengths and weaknesses, and some examples of how each method has been applied to the analysis of complex signaling networks. When applied correctly, each of these techniques can provide insight into the topology, dynamics, and regulation of protein phosphorylation signaling networks.
Cellular Homeostasis and Aging
Authors: Hartl F. Ulrich
Published: April 2016

Aging and longevity are controlled by a multiplicity of molecular and cellular signaling events that interface with environmental factors to maintain cellular homeostasis. Modulation of these pathways to extend life span, including insulin-like signaling and the response to dietary restriction, identified the cellular machineries and networks of protein homeostasis (proteostasis) and stress resistance pathways as critical players in the aging process. A decline of proteostasis capacity during aging leads to dysfunction of specific cell types and tissues, rendering the organism susceptible to a range of chronic diseases. This volume of the Annual Review of Biochemistry contains a set of two reviews addressing our current understanding of the molecular mechanisms underlying aging in model organisms and humans.
Experimental Milestones in the Discovery of Molecular Chaperones as Polypeptide Unfolding Enzymes
Authors: Finka Andrija , Mattoo Rayees U.H. , Goloubinoff Pierre
Published: April 2016

Molecular chaperones control the cellular folding, assembly, unfolding, disassembly, translocation, activation, inactivation, disaggregation, and degradation of proteins. In 1989, groundbreaking experiments demonstrated that a purified chaperone can bind and prevent the aggregation of artificially unfolded polypeptides and use ATP to dissociate and convert them into native proteins. A decade later, other chaperones were shown to use ATP hydrolysis to unfold and solubilize stable protein aggregates, leading to their native refolding. Presently, the main conserved chaperone families Hsp70, Hsp104, Hsp90, Hsp60, and small heat-shock proteins (sHsps) apparently act as unfolding nanomachines capable of converting functional alternatively folded or toxic misfolded polypeptides into harmless protease-degradable or biologically active native proteins. Being unfoldases, the chaperones can proofread three-dimensional protein structures and thus control protein quality in the cell. Understanding the mechanisms of the cellular unfoldases is central to the design of new therapies against aging, degenerative protein conformational diseases, and specific cancers.
Regulation of mitogen-activated protein kinase by protein kinase C and mitogen-activated protein kinase phosphatase-1 in vascular smooth muscle
Authors: Trappanese Danielle M. , Sivilich Sarah , Ets Hillevi K. , Kako Farah , Autieri Michael V. , Moreland Robert S.
Published: April 2016

Vascular smooth muscle contraction is primarily regulated by phosphorylation of myosin light chain. There are also modulatory pathways that control the final level of force development. We tested the hypothesis that protein kinase C (PKC) and mitogen-activated protein (MAP) kinase modulate vascular smooth muscle activity via effects on MAP kinase phosphatase-1 (MKP-1). Swine carotid arteries were mounted for isometric force recording and subjected to histamine stimulation in the presence and absence of inhibitors of PKC [bisindolylmaleimide-1 (Bis)], MAP kinase kinase (MEK) (U0126), and MKP-1 (sanguinarine) and flash frozen for measurement of MAP kinase, PKC-potentiated myosin phosphatase inhibitor 17 (CPI-17), and caldesmon phosphorylation levels. CPI-17 was phosphorylated in response to histamine and was inhibited in the presence of Bis. Caldesmon phosphorylation levels increased in response to histamine stimulation and were decreased in response to MEK inhibition but were not affected by the addition of Bis. Inhibition of PKC significantly increased p42 MAP kinase, but not p44 MAP kinase. Inhibition of MEK with U0126 inhibited both p42 and p44 MAP kinase activity. Inhibition of MKP-1 with sanguinarine blocked the Bis-dependent increase of MAP kinase activity. Sanguinarine alone increased MAP kinase activity due to its effects on MKP-1. Sanguinarine increased MKP-1 phosphorylation, which was inhibited by inhibition of MAP kinase. This suggests that MAP kinase has a negative feedback role in inhibiting MKP-1 activity. Therefore, PKC catalyzes MKP-1 phosphorylation, which is reversed by MAP kinase. Thus the fine tuning of vascular contraction is due to the concerted effort of PKC, MAP kinase, and MKP-1.
Activation of mTORC1 by leucine is potentiated by branched-chain amino acids and even more so by essential amino acids following resistance exercise
Authors: Moberg Marcus , Apró William , Ekblom Björn , van Hall Gerrit , Holmberg Hans-Christer , Blomstrand Eva
Published: April 2016

Protein synthesis is stimulated by resistance exercise and intake of amino acids, in particular leucine. Moreover, activation of mammalian target of rapamycin complex 1 (mTORC1) signaling by leucine is potentiated by the presence of other essential amino acids (EAA). However, the contribution of the branched-chain amino acids (BCAA) to this effect is yet unknown. Here we compare the stimulatory role of leucine, BCAA, and EAA ingestion on anabolic signaling following exercise. Accordingly, eight trained volunteers completed four sessions of resistance exercise during which they ingested either placebo, leucine, BCAA, or EAA (including the BCAA) in random order. Muscle biopsies were taken at rest, immediately after exercise, and following 90 and 180 min of recovery. Following 90 min of recovery the activity of S6 kinase 1 (S6K1) was greater than at rest in all four trials (Placebo<Leucine<BCAA<EAA; P < 0.05 time × supplement), with a ninefold increase in the EAA trial. At this same time point, phosphorylation of eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) at Thr37/46 was unaffected by supplementation, while that of Thr46 alone exhibited a pattern similar to that of S6K1, being 18% higher with EAA than BCAA. However, after 180 min of recovery this difference between EAA and BCAA had disappeared, although with both these supplements the increases were still higher than with leucine (40%, P < 0.05) and placebo (100%, P < 0.05). In summary, EAA ingestion appears to stimulate translation initiation more effectively than the other supplements, although the results also suggest that this effect is primarily attributable to the BCAA.
Therapeutic effects and mechanism of conditioned media from human mesenchymal stem cells on anti-GBM glomerulonephritis in WKY rats
Authors: Iseri Ken , Iyoda Masayuki , Ohtaki Hirokazu , Matsumoto Kei , Wada Yukihiro , Suzuki Taihei , Yamamoto Yasutaka , Saito Tomohiro , Hihara Kei , Tachibana Shohei , Honda Kazuho , Shibata Takanori
Published: April 2016

Recent studies have demonstrated that conditioned media derived from mesenchymal stem cells (MSC-CM) have therapeutic effects in various experimental diseases. However, the therapeutic mechanism is not fully understood. In the present study, we investigated the therapeutic effects and mechanism of MSC-CM in experimental antiglomerular basement membrane glomerulonephritis. We administered either MSC-CM or vehicle from day 0 to day 10 after the induction of nephrotoxic serum nephritis in Wistar-Kyoto rats. In vitro, we analyzed the effects of MSC-CM on TNF-α-mediated cytokine production in cultured normal human mesangial cells, proximal tubular (HK-2) cells, human umbilical vein endothelial cells, and monocytes (THP-1 and peripheral blood mononuclear cells). Compared with vehicle treatment, MSC-CM treatment improved proteinuria and renal dysfunction. Histologically, MSC-CM-treated rats had reduced crescent formation and glomerular ED1+macrophage infiltration and increased glomerular ED2+macrophage infiltration. Increased serum monocyte chemoattractant protein (MCP)-1 levels were observed in MSC-CM-treated rats. Renal cortical mRNA expression levels of proinflammatory cytokines, such as TNF-α and IL-6, and of the T helper cell 1 cytokine interferon-γ were greatly decreased by MSC-CM treatment. In vitro, pretreatment with MSC-CM blocked TNF-α-mediated IL-8 release in normal human mesangial cells and HK-2 cells. TNF-α-mediated MCP-1 release was enhanced by pretreatment with MSC-CM in human umbilical vein endothelial cells and HK-2 cells and was strikingly enhanced in THP-1 cells. Stimulation of peripheral blood mononuclear cells with a combination of MCP-1 and IL-4 enhanced the expression of M2-associated genes compared with IL-4 alone. We demonstrated that MSC-CM had therapeutic effects in experimental antiglomerular basement membrane glomerulonephritis that were mediated through anti-inflammatory effects that were partly due to acceleration of M2 macrophage polarization, which might be mediated by MCP-1 enhancement.
Contracting for Competitive Supply Chains under Network Externalities and Demand Uncertainty
Authors: Liu Xiaojing
Published: April 2016

Based on network externalities and demand uncertainty environment, supply chain competition model is built; we identify the valid mechanism for the alternative range of profit-sharing contracts and also analyze the effect of product substitutability coefficient and network externalities on the alliance and profit-sharing contract. The results show that the vertical alliance contributes profit improvement to both the manufacturer and the retailer when the impact of network externalities on the product substitutability is not strong. However, vertical alliance will be out of operation when the effect of network externalities on the product substitutability is strong.
National Environmental Meteorological Services in China
Authors: Kang Zhiming , Gui Hailin , Hua Cong , Zhang Bihui , Zhang Hengde , Lv Mengyao , Wang Jikang
Published: April 2016

The environmental meteorological services in China are concerned with atmospheric environmental quality, which is directly related to human activities and affects human health. In recent years, air pollution and other environmental problems have attracted nationwide attention in China, so the environmental meteorological services have been developed rapidly. To provide better meteorological monitoring and forecasting services, the Environmental Meteorological Centre of China Meteorological Administration was established in March 2014 by integrating the resources of various national service units. We review the development of China’s national environmental meteorological services and highlight their current status including major technological capabilities. We also explore future trends of the national environmental meteorological services by analysing deficiencies, gaps in supply and demand, and capabilities of the current environmental meteorological services.
Clinical Performance of Toris K Contact Lens in Patients with Moderate to Advanced Keratoconus: A Real Life Retrospective Analysis
Authors: Yilmaz Ihsan , Ozcelik Ferah , Basarir Berna , Demir Gokhan , Durusoy Gonul , Taskapili Muhittin
Published: April 2016

Objectives.To evaluate the visual performance of Toris K soft contact lenses in patients with moderate-to-advanced keratoconus and also to compare the results according to cone types, cone location, and severity of keratoconus.Materials and Methods.Sixty eyes of 40 participants were included in this retrospective study. Uncorrected visual acuity (UCVA), best-spectacle corrected visual acuity (BCVA), best-contact lens corrected visual acuity (BCLCVA), and comfort rating via visual analogue scales (VAS) were measured.Results.The mean age was 27.3 ± 8.6 years (range: 18 to 54). The mean logMAR UCVA, BCVA, and BCLCVA were 0.85 ± 0.38 (range: 0.30–1.30), 0.47 ± 0.27 (range: 0.10–1.30), and 0.16 ± 0.20 (range: 0–1.00). There were significant increases in visual acuities with contact lenses (p<.05). BCLCVA was significantly better in oval type than globus type (p=.022). UCVA and BCLCVA were significantly better in moderate keratoconus group (p=.015,p=.018). The mean line gain in Snellen was 3.6 ± 1.8 lines (range: 0–7 lines). The mean line gain was higher in central cone group than paracentral cone group and oval group than globus group (p=.014,p=.045). The mean VAS score was 8.14 ± 1.88 (range: 6–10).Conclusions.Toris K can improve visual acuity of patients with keratoconus. Toris K is successful even in the moderate and advanced form of the disease.
The Reactive Oxygen Species in Macrophage Polarization: Reflecting Its Dual Role in Progression and Treatment of Human Diseases
Authors: Tan Hor-Yue , Wang Ning , Li Sha , Hong Ming , Wang Xuanbin , Feng Yibin
Published: April 2016

High heterogeneity of macrophage is associated with its functions in polarization to different functional phenotypes depending on environmental cues. Macrophages remain in balanced state in healthy subject and thus macrophage polarization may be crucial in determining the tissue fate. The two distinct populations, classically M1 and alternatively M2 activated, representing the opposing ends of the full activation spectrum, have been extensively studied for their associations with several disease progressions. Accumulating evidences have postulated that the redox signalling has implication in macrophage polarization and the key roles of M1 and M2 macrophages in tissue environment have provided the clue for the reasons of ROS abundance in certain phenotype. M1 macrophages majorly clearing the pathogens and ROS may be crucial for the regulation of M1 phenotype, whereas M2 macrophages resolve inflammation which favours oxidative metabolism. Therefore how ROS play its role in maintaining the homeostatic functions of macrophage and in particular macrophage polarization will be reviewed here. We also review the biology of macrophage polarization and the disturbance of M1/M2 balance in human diseases. The potential therapeutic opportunities targeting ROS will also be discussed, hoping to provide insights for development of target‐specific delivery system or immunomodulatory antioxidant for the treatment of ROS‐related diseases.
Altered Levels of Serum Zinc and Cadmium in Patients with Chronic Vesiculobullous Hand and Feet Dermatitis
Authors: Suvirya Swastika , Thakur Alpna , Pandey S. S. , Tripathi S. K. , Dwivedi Durgesh Kumar
Published: April 2016

Micronutrients serve many important functions in our body and altered levels of heavy and trace metals are associated with cutaneous and systemic disorders. Vesicular palmoplantar eczema is an entity whose etiopathogenesis is a mystery. In this prospective case-noncase study blood levels of Zinc and Cadmium in 37 patients of chronic vesiculobullous hand dermatitis were estimated and compared with 40 noncases with similar age and gender distributions. Low serum Zinc levels were found in patients as compared to noncases. The mean difference of serum Zinc between the case and noncase groups was 27.26; the mean value of serum Zinc between the two groups was statistically significant (p<0.0001). However, elevated Cadmium levels were detected in only 5 patients and in none of the noncases. The mean concentration of serum Cadmium was2.32±0.38 μg/dL, with a range of 1.90–2.80 μg/dL for the five cases in whom Cadmium was detected. Various toxic and trace metals can interact by influencing each other’s absorption, retention, distribution, and bioavailability in the body. The clinical significance of this finding lies in the possible beneficial role of Zinc supplementation in the therapy of chronic vesiculobullous hand dermatitis.
Protective Effects of Melatonin on Retinal Inflammation and Oxidative Stress in Experimental Diabetic Retinopathy
Authors: Jiang Tingting , Chang Qing , Cai Jiyang , Fan Jiawen , Zhang Xiaozhe , Xu Gezhi
Published: April 2016

Oxidative stress and inflammation are important pathogenic factors contributing to the etiology of diabetic retinopathy (DR). Melatonin is an endogenous hormone that exhibits a variety of biological effects including antioxidant and anti‐inflammatory functions. The goals of this study were to determine whether melatonin could ameliorate retinal injury and to explore the potential mechanisms. Diabetes was induced by a single intraperitoneal (i.p.) injection of STZ (60 mg/kg) in Sprague‐Dawley rats. Melatonin (10 mg kg−1 daily, i.p.) was administered from the induction of diabetes and continued for up to 12 weeks, after which the animals were sacrificed and retinal samples were collected. The retina of diabetic rats showed depletion of glutathione and downregulation of glutamate cysteine ligase (GCL). Melatonin significantly upregulated GCL by retaining Nrf2 in the nucleus and stimulating Akt phosphorylation. The production of proinflammatory cytokines and proteins, including interleukin 1β, TNF‐α, and inducible nitric oxide synthase (iNOS), was inhibited by melatonin through the NF‐κB pathway. At 12 weeks, melatonin prevented the significant decrease in the ERG a‐ and b‐wave amplitudes under the diabetic condition. Our results suggest potent protective functions of melatonin in diabetic retinopathy. In addition to being a direct antioxidant, melatonin can exert receptor‐mediated signaling effects to attenuate inflammation and oxidative stress of the retina.