bluuebunny/crossref_metadata_2025 huggingface dataset:
AUTOMATIC THEOREM-PROVING IN COMBINATORICS ON WORDS
Authors: GOČ DANIEL , HENSHALL DANE , SHALLIT JEFFREY
Published: December 2013

We describe a technique for mechanically proving certain kinds of theorems in combinatorics on words, using finite automata and a software package for manipulating them. We illustrate our technique by applying it to (a) solve an open problem of Currie and Saari on the lengths of unbordered factors in the Thue-Morse sequence; (b) verify an old result of Prodinger and Urbanek on the regular paperfolding sequence; (c) find an explicit expression for the recurrence function for the Rudin-Shapiro sequence; and (d) improve the avoidance bound in Leech's squarefree sequence. We also introduce a new measure of infinite words called condensation and compute it for some famous sequences. We follow up on the study of Currie and Saari of least periods of infinite words. We show that the characteristic sequence of least periods of a k-automatic sequence is (effectively) k-automatic. We compute the least periods for several famous sequences. Many of our results were obtained by machine computations.
HOW TO SYNCHRONIZE THE HEADS OF A MULTITAPE AUTOMATON
Authors: IBARRA OSCAR H. , TRAN NICHOLAS Q.
Published: December 2013

Given an n-tape automaton M with a one-way read-only head per tape and a right end marker $ on each tape, we say that M is aligned or 0-synchronized (or simply, synchronized) if for every n-tuple x = (x1,…, xn) that is accepted, there is a computation on x such that at any time during the computation, all heads, except those that have reached the end marker, are on the same position. When a head reaches the marker, it can no longer move. As usual, an n-tuple x = (x1,…, xn) is accepted if M eventually reaches the configuration where all n heads are on $ in an accepting state. In two recent papers, we looked at the problem of deciding, given an n-tape automaton of a given type, whether there exists an equivalent synchronized n-tape automaton of the same type. In this paper, we exhibit various classes of multitape automata which can(not) be converted to equivalent synchronized multitape automata.
ON THE DISAMBIGUATION OF FINITE AUTOMATA AND FUNCTIONAL TRANSDUCERS
Authors: MOHRI MEHRYAR
Published: December 2013

This paper introduces a new disambiguation algorithm for finite automata and functional finite-state transducers. It gives a full description of this algorithm, including a detailed pseudocode and analysis, and several illustrating examples. The algorithm is often more efficient and the result dramatically smaller than the one obtained using determinization for finite automata or the construction of Schützenberger. The unambiguous automaton or transducer created by our algorithm are never larger than those generated by the construction of Schützenberger. In fact, in a variety of cases, the size of the unambiguous transducer returned by our algorithm is only linear in that of the input transducer while the transducer created by the construction of Schützenberger is exponentially larger. Our algorithm can be used effectively in many applications to make automata and transducers more efficient to use.
RATIONAL MULTI-SECRET SHARING SCHEME IN STANDARD POINT-TO-POINT COMMUNICATION NETWORKS
Authors: ZHANG EN , CAI YONGQUAN
Published: December 2013

Rational secret sharing was first introduced by Halpern and Teague (STOC, 2004). Since then, a series of works have focused on designing rational secret sharing protocols. However, most existing solutions can share only one secret at one secret sharing process. To share multiple secrets such as m secrets, the dealer must redistribute shares for m times. In addition, previous works assume existence of broadcast channel which is not realistic. Motivated by those problems, this paper proposes a rational multi-secret sharing scheme, which combines the secret sharing scheme with game theory. In the protocol, the problem of sharing multiple secrets is addressed, and there are multiple secrets to be shared during one secret sharing process. Furthermore, this work starts off by constructing a protocol in simultaneous broadcast networks, and then we emulate the broadcast channel over point-to-point networks. Based on a computational assumption, we show that rational players have no incentive to deviate from the protocol and every player can obtain multi-secret fairly.
A NEW UPPER BOUND FOR RANDOM (2 + p)-SAT BY FLIPPING TWO VARIABLES
Authors: ZHOU GUANGYAN , GAO ZONGSHENG
Published: December 2013

The random (2 + p)-SAT model has been proposed [18] to study the possible relation between the “order” of phase transitions and computational complexity. It was also claimed that there exists pc > 0, such that for p < pc the random (2 + p)-SAT instance behaves like 2-SAT. Later, Achlioptas et al. [3] obtained the first rigorous results that 0.4 ≤ pc ≤ 0.695, the methods they use are the first moment method and the simple Unit-Clause algorithm. In this paper, we try to optimize the local maximality condition of the truth assignments when implementing the first moment method. We prove that the phase transition point of clauses-to-variables ratio r (dependent on p) can be improved. Moreover, we show that the upper bound of pc can be reduced to 0.6846. This fact implies that, for a constant λ < 1, a random (2 + p)-SAT formula with λn 2-clauses and 2.17n 3-clauses is almost surely unsatisfiable.
THE SUPER SPANNING CONNECTIVITY AND SUPER SPANNING LACEABILITY OF TORI WITH FAULTY ELEMENTS
Authors: LI JING , LIU DI , YUAN JUN
Published: December 2013

A k-container of a graph G is a set of k internally disjoint paths between two distinct vertices. A k-container of G is a k*-container if it contains all vertices of G. A graph G is k*-connected if there exists a k*-container between any two distinct vertices, and a bipartite graph G is k*-laceable if there exists a k*-container between any two vertices from different partite sets of G. A k-connected graph (respectively, bipartite graph) G is super spanning connected (respectively, laceable) if G is r*-connected (r*-laceable) for any r with 1 ≤ r ≤ k. This paper shows that the two-dimensional torus Torus (m, n), m, n ≥ 3, is super spanning connected if at least one of m and n is odd and super spanning laceable if both m and n are even. Furthermore, the super spanning connectivity and spanning laceability of tori with faulty elements have been discussed.
BCS–BEC CROSSOVER IN RELATIVISTIC FERMI SYSTEMS
Authors: HE LIANYI , MAO SHIJUN , ZHUANG PENGFEI
Published: December 2013

We review the BCS–BEC crossover in relativistic Fermi systems, including the QCD matter at finite density. In the first part, we study the BCS–BEC crossover in a relativistic four-fermion interaction model and show how the relativistic effect affects the BCS–BEC crossover. In the second part, we investigate both two-color QCD at finite baryon density and pion superfluid at finite isospin density, by using an effective Nambu–Jona–Lasinio model. We will show how the model describes the weakly interacting diquark and pion condensates at low density and the BEC–BCS crossover at high density.
Hilbert transform of G-Brownian local time
Authors: Yan Litan , Zhang Qinghua , Gao Bo
Published: December 2013

Let B be a G-Brownian motion with quadratic process 〈B〉 under the G-expectation. In this paper, we consider the integrals [Formula: see text] We show that the integral diverges and the convergence [Formula: see text] exists in 𝕃2 for all a ∈ ℝ, t > 0. This shows that [Formula: see text] coincides with the Hilbert transform of the local time [Formula: see text] of G-Brownian motion B for every t. The functional is a natural extension to classical cases. As a natural result we get a sublinear version of Yamada's formula [Formula: see text] where the integral is the Itô integral under the G-expectation.
A coupling approach to random circle maps expanding on the average
Authors: Stenlund Mikko , Sulku Henri
Published: December 2013

We study random circle maps that are expanding on the average. Uniform bounds on neither expansion nor distortion are required. We construct a coupling scheme, which leads to exponential convergence of measures (memory loss) and exponential mixing. Leveraging from the structure of the associated correlation estimates, we prove an almost sure invariance principle for vector-valued observables. The motivation for our paper is to explore these methods in a non-uniform random setting.
MICROENTERPRISE GROWTH AT THE BASE OF THE PYRAMID: A RESOURCE-BASED PERSPECTIVE
Authors: WEBB JUSTIN W. , MORRIS MICHAEL H. , PILLAY RUBIN
Published: December 2013

In a base-of-the-pyramid context, the ability to start ventures is often quite robust because micro-entrepreneurs are able to start with few resources and can often sustain ventures for extended lengths of time in the absence of meaningful revenues. Yet, the ability to grow ventures tends to be much more problematic. This paper examines the role of resources in yielding competitive advantage for microenterprises in base-of-the-pyramid markets, arguing that the value of resources is a function of their ability to supplement formal institutional voids. We consider access to formal infrastructure, assets that provide stability and business skills as potential sources of competitive advantage. We also examine the effect of resource allocation tactics on microenterprise growth. We test our theory using a sample of South African microenterprise owners. Implications are drawn for ongoing theory development and practice.
UNORGANIZED SECTOR IN INDIA: EMPLOYMENT ELASTICITY AND WAGE-PRODUCTIVITY NEXUS
Authors: MITRA ARUP , PANDEY AVIRAL
Published: December 2013

In India the formal, or organized, sector is not able to generate employment opportunities for the unskilled or semi-skilled workers on a large scale, forcing them to get residually absorbed in the unorganized sector. At the same time, the unorganized sector is believed to have work consignments from the organized sector and this ancillarization process is contributing to employment creation. In the backdrop of these views the present study, using the unit level data of the National Sample Survey (NSS, 2010-11), makes an attempt to estimate the employment elasticity and wage-productivity nexus in the unorganized sector. Although the employment function estimated in the paper suggests employment can be raised through wage reduction, it can affect the wellbeing of the workers because the wage rate in the unorganized sector is already very low. Further, subcontracting or ancillarization does not seem to be contributing to employment generation in unorganized manufacturing or trade related activities. However, in the services sector it shows a positive impact. The equation representing determinants of wages shows units with assets are better-off compared to those that do not have them. This has an important policy implication, suggesting that through asset creation, government may bring in improvements in livelihood of the unorganized sector enterprises.
COMPUTATIONAL HOMOGENIZATION OF POLYCRYSTALLINE MATERIALS WITH PORES: A THREE-DIMENSIONAL GRAIN BOUNDARY FORMULATION
Authors: TRENTACOSTE F. , BENEDETTI I. , ALIABADI M. H.
Published: December 2013

In this study, the influence of porosity on the elastic effective properties of polycrystalline materials is investigated using a 3D grain boundary micro mechanical model. The volume fraction of pores, their size and distribution can be varied to better simulate the response of real porous materials. The formulation is built on a boundary integral representation of the elastic problem for the grains, which are modeled as 3D linearly elastic orthotropic domains with arbitrary spatial orientation. The artificial polycrystalline morphology is represented using 3D Voronoi Tessellations. The formulation is expressed in terms of intergranular fields, namely displacements and tractions that play an important role in polycrystalline micromechanics. The continuity of the aggregate is enforced through suitable intergranular conditions. The effective material properties are obtained through material homogenization, computing the volume averages of micro-strains and stresses and taking the ensemble average over a certain number of microstructural samples. The obtained results show the capability of the model to assess the macroscopic effects of porosity.
China's Low Carbon Transformation
Authors: PAN Jiahua , ZHANG Ying
Published: December 2013

Along with industrialization and urbanization processes, China's emission of greenhouse gases has been increasing rapidly and substantially over the past 40 years, as measured in aggregate and in per capita terms. While there are reasons to drive up the emissions, the Chinese government has made efforts to lower the rate of increase in emissions, as emission reduction is consistent with China's pursuit for energy security and sustainable development. Ambitious targets and aggressive actions have been made in China to accelerate the process of low carbon transformation. However, challenges remain and additional policies will be required to accomplish the process of low carbon transformation.
China's Industrialization Process: Stage, Feature, and Prospect
Authors: HUANG Qunhui
Published: December 2013

Becoming an industrialized country is a necessary requirement for the Chinese nation to realize great rejuvenation, and it is also an important economy connotation to achieve the “Chinese Dream”. This paper holds that after the past 30 years' the rapid development of China since adopting reform and opening up policy, China's industrialization has been in its late stage now. China's industrialization, so far, has been developing into a great nation with a population of over one billion, and is advancing rapidly. It is now facing a highly unbalanced regional development. It is also a low-cost and export-oriented industrialization. This kind of industrialization is unprecedented in all of human history. The prospects of China's industrialization are bright. China, developing normally, could accomplish industrialization in 2025 to 2030 at the latest. However, the industrialization process may not be smooth. After the financial crisis, the third industrial revolution and servitization in manufacturing have been important trends in the global industrialization process, which would make for smooth progress of China's industrialization more difficult, and increasing the need for strategic adjustment of China's industrialization.
Cholera toxin enhances Na+ absorption across MCF10A human mammary epithelia
Authors: Wang Qian , Schultz Bruce D.
Published: December 2013

Cellular mechanisms to account for the low Na+ concentration in human milk are poorly defined. MCF10A cells, which were derived from human mammary epithelium and grown on permeable supports, exhibit amiloride- and benzamil-sensitive short-circuit current ( Isc; a sensitive indicator of net ion transport), suggesting activity of the epithelial Na+ channel ENaC. When cultured in the presence of cholera toxin (Ctx), MCF10A cells exhibit greater amiloride-sensitive Isc at all time points tested (2 h to 7 days), an effect that is not reduced with Ctx washout for 12 h. Amiloride-sensitive Isc remains elevated by Ctx in the presence of inhibitors for PKA (H-89, Rp-cAMP), PI3K (LY294002), and protein trafficking (brefeldin A). Additionally, the Ctx B subunit, alone, does not replicate these effects. RT-PCR and Western blot analyses indicate no significant increase in either the mRNA or protein expression for α-, β-, or, γ-ENaC subunits. Ctx increases the abundance of both β- and γ-ENaC in the apical membrane. Additionally, Ctx increases both phosphorylated and nonphosphorylated Nedd4-2 expression. These results demonstrate that human mammary epithelia express ENaC, which can account for the low Na+ concentration in milk. Importantly, the results suggest that Ctx increases the expression but reduces the activity of the E3 ubiquitin ligase Nedd4-2, which would tend to reduce the ENaC retrieval and increase steady-state membrane residency. The results reveal a novel mechanism in human mammary gland epithelia by which Ctx regulates ENaC-mediated Na+ transport, which may have inferences for epithelial ion transport regulation in other tissues throughout the body.
Grape-seed procyanidins modulate cellular membrane potential and nutrient-induced GLP-1 secretion in STC-1 cells
Authors: González-Abuín Noemi , Martínez-Micaelo Neus , Blay Mayte , Green Brian D. , Pinent Montserrat , Ardévol Anna
Published: December 2013

Grape-seed procyanidin extracts (GSPE) modulate glucose homeostasis, and it was suggested that GSPE may achieve this by enhancing the secretion of incretin hormones such as glucagon-like peptide-1 (GLP-1). Therefore, the aim of the present study is to examine in detail the effects of GSPE on intestinal endocrine cells (STC-1). GSPE was found to modulate plasma membrane potential in enteroendocrine cells, inducing depolarization at low concentrations (0.05 mg/l) and hyperpolarization at high concentrations (50 mg/l), and surprisingly this was also accompanied by suppressed GLP-1 secretion. Furthermore, how GSPE affects STC-1 cells under nutrient-stimulated conditions (i.e., glucose, linoleic acid, and l-proline) was also explored, and we found that the higher GSPE concentration was effective in limiting membrane depolarization and reducing GLP-1 secretion. Next, it was also examined whether GSPE affected mitochondrial membrane potential, and it was found that this too is altered by GSPE; however, this does not appear to explain the observed effects on plasma membrane potential and GLP-1 secretion. In conclusion, our results show that grape-seed procyanidins modulate cellular membrane potential and nutrient-induced enteroendocrine hormone secretion in STC-1 cells.
Aberrant expression of laminin-332 promotes cell proliferation and cyst growth in ARPKD
Authors: Vijayakumar Soundarapandian , Dang Suparna , Marinkovich M. Peter , Lazarova Zelmira , Yoder Bradley , Torres Vicente E. , Wallace Darren P.
Published: December 2013

Basement membrane abnormalities have often been observed in kidney cysts of polycystic kidney disease (PKD) patients and animal models. There is an abnormal deposition of extracellular matrix molecules, including laminin-α3,β3,γ2 (laminin-332), in human autosomal dominant PKD (ADPKD). Knockdown of PKD1 paralogs in zebrafish leads to dysregulated synthesis of the extracellular matrix, suggesting that altered basement membrane assembly may be a primary defect in ADPKD. In this study, we demonstrate that laminin-332 is aberrantly expressed in cysts and precystic tubules of human autosomal recessive PKD (ARPKD) kidneys as well as in the kidneys of PCK rats, an orthologous ARPKD model. There was aberrant expression of laminin-γ2 as early as postnatal day 2 and elevated laminin-332 protein in postnatal day 30, coinciding with the formation and early growth of renal cysts in PCK rat kidneys. We also show that a kidney cell line derived from Oak Ridge polycystic kidney mice, another model of ARPKD, exhibited abnormal lumen-deficient and multilumen structures in Matrigel culture. These cells had increased proliferation rates and altered expression levels of laminin-332 compared with their rescued counterparts. A function-blocking polyclonal antibody to laminin-332 significantly inhibited their abnormal proliferation rates and rescued their aberrant phenotype in Matrigel culture. Furthermore, abnormal laminin-332 expression in cysts originating from collecting ducts and proximal tubules as well as in precystic tubules was observed in a human end-stage ADPKD kidney. Our results suggest that abnormal expression of laminin-332 contributes to the aberrant proliferation of cyst epithelial cells and cyst growth in genetic forms of PKD.
Tongxinluo ameliorates renal structure and function by regulating miR-21-induced epithelial-to-mesenchymal transition in diabetic nephropathy
Authors: Wang Jin-yang , Gao Yan-bin , Zhang Na , Zou Da-wei , Xu Li-ping , Zhu Zhi-yao , Li Jiao-yang , Zhou Sheng-nan , Cui Fang-qiang , Zeng Xiang-jun , Geng Jian-guo , Yang Jin-kui
Published: December 2013

Diabetic nephropathy (DN) is one of the most important diabetic microangiopathies. The epithelial-to-mesenchymal transition (EMT) plays an important role in DN. The physiological role of microRNA-21 (miR-21) was closely linked to EMT. However, it remained elusive whether tongxinluo (TXL) ameliorated renal structure and function by regulating miR-21-induced EMT in DN. This study aimed to determine the effect of TXL on miR-21-induced renal tubular EMT and to explore the relationship between miR-21 and TGF-β1/smads signals. Real-time RT-PCR, cell transfection, in situ hybridization (ISH), and laser confocal microscopy were used, respectively. Here, we revealed that TXL dose dependently lowered miR-21 expression in tissue, serum, and cells. Overexpression of miR-21 can enhance α-smooth muscle actin (SMA) expression and decrease E-cadherin expression by upregulating smad3/p-smad3 expression and downregulating smad7 expression. Interestingly, TXL also increased E-cadherin expression and decreased α-SMA expression by regulating miR-21 expression. More importantly, TXL decreased collagen IV, fibronectin, glomerular basement membrane, glomerular area, and the albumin/creatinine ratio, whereas it increased the creatinine clearance ratio. The results demonstrated that TXL ameliorated renal structure and function by regulating miR-21-induced EMT, which was one of the mechanisms to protect against DN, and that miR-21 may be one of the therapeutic targets for TXL in DN.
Vulnerability of neonatal respiratory neural control to sustained hypoxia during a uniquely sensitive window of development
Authors: Mayer C. A. , Di Fiore J. M. , Martin R. J. , MacFarlane P. M.
Published: December 2013

The first postnatal weeks represent a period of development in the rat during which the respiratory neural control system may be vulnerable to aberrant environmental stressors. In the present study, we investigated whether sustained hypoxia (SH; 11% O2) exposure starting at different postnatal ages differentially modifies the acute hypoxic (HVR) and hypercapnic ventilatory response (HCVR). Three different groups of rat pups were exposed to 5 days of SH, starting at either postnatal age 1 (SH1–5), 11 (SH11–15), or 21 (SH21–25) days. Whole body plethysmography was used to assess the HVR and HCVR the day after SH exposure ended. The primary results indicated that 1) the HVR and HCVR of SH11–15rats were absent or attenuated (respectively) compared with age-matched rats raised in normoxia; 2) there was a profoundly high (∼84% of pups) incidence of unexplained mortality in the SH11–15rats; and 3) these phenomena were unique to the SH11–15group with no comparable effect of the SH exposure on the HVR, HCVR, or mortality in the younger (SH1–5) or older (SH21–25) rats. These results share several commonalities with the risk factors thought to underlie the etiology of sudden infant death syndrome, including 1) a vulnerable neonate; 2) a critical period of development; and 3) an environmental stressor.
Physiology in Medicine: Acute altitude exposure in patients with pulmonary and cardiovascular disease
Authors: Seccombe Leigh M. , Peters Matthew J.
Published: December 2013

Travel is more affordable and improved high-altitude airports, railways, and roads allow rapid access to altitude destinations without acclimatization. The physiology of exposure to altitude has been extensively described in healthy individuals; however, there is a paucity of data pertaining to those who have reduced reserve. This Physiology in Medicine article discusses the physiological considerations relevant to the safe travel to altitude and by commercial aircraft in patients with pulmonary and/or cardiac disease.
Plantar flexor moment arm and muscle volume predict torque-generating capacity in young men
Authors: Baxter Josh R. , Piazza Stephen J.
Published: December 2013

Muscle volume is known to correlate with maximal joint torque in humans, but the role of muscle moment arm in determining maximal torque is less clear. Moderate correlations have been reported between maximal isometric knee extensor torque and knee extensor moment arm, but no such observations have been made for the ankle joint. It has been suggested that smaller muscle moment arms may enhance force generation at high rates of joint rotation, but this has not yet been observed for ankle muscles in vivo. The purpose of the present study was to correlate plantar flexor moment arm and plantar flexor muscle volume with maximal plantar flexor torque measured at different rates of plantar flexion. Magnetic resonance imaging was used to quantify the plantar flexor moment arm and muscle volume of the posterior compartment in 20 healthy young men. Maximal plantar flexor torque was measured isometrically and at three plantar flexion speeds using an isokinetic dynamometer. Plantar flexor torque was significantly correlated with muscle volume (0.222 < R2< 0.322) and with muscle moment arm at each speed (0.323 < R2< 0.494). While muscle volume was strongly correlated with body mass and stature, moment arm was not. The slope of the torque-moment arm regression line decreased as the rate of joint rotation increased, indicating that subjects with small moment arms experienced smaller reductions in torque at high speeds. The findings of this study suggest that plantar flexor moment arm is a determinant of joint strength that is at least as important as muscle size.
Hindlimb heating increases vascular access of large molecules to murine tibial growth plates measured by in vivo multiphoton imaging
Authors: Serrat Maria A. , Efaw Morgan L. , Williams Rebecca M.
Published: December 2013

Advances in understanding the molecular regulation of longitudinal growth have led to development of novel drug therapies for growth plate disorders. Despite progress, a major unmet challenge is delivering therapeutic agents to avascular-cartilage plates. Dense extracellular matrix and lack of penetrating blood vessels create a semipermeable “barrier,” which hinders molecular transport at the vascular-cartilage interface. To overcome this obstacle, we used a hindlimb heating model to manipulate bone circulation in 5-wk-old female mice ( n = 22). Temperatures represented a physiological range of normal human knee joints. We used in vivo multiphoton microscopy to quantify temperature-enhanced delivery of large molecules into tibial growth plates. We tested the hypothesis that increasing hindlimb temperature from 22°C to 34°C increases vascular access of large systemic molecules, modeled using 10, 40, and 70 kDa dextrans that approximate sizes of physiological regulators. Vascular access was quantified by vessel diameter, velocity, and dextran leakage from subperichondrial plexus vessels and accumulation in growth plate cartilage. Growth plate entry of 10 kDa dextrans increased >150% at 34°C. Entry of 40 and 70 kDa dextrans increased <50%, suggesting a size-dependent temperature enhancement. Total dextran levels in the plexus increased at 34°C, but relative leakage out of vessels was not temperature dependent. Blood velocity and vessel diameter increased 118% and 31%, respectively, at 34°C. These results demonstrate that heat enhances vascular carrying capacity and bioavailability of large molecules around growth plates, suggesting that temperature could be a noninvasive strategy for modulating delivery of therapeutics to impaired growth plates of children.
Do monkey F5 mirror neurons show changes in firing rate during repeated observation of natural actions?
Authors: Kilner J. M. , Kraskov A. , Lemon R. N.
Published: December 2013

Mirror neurons were first discovered in area F5 of macaque monkeys. In humans, noninvasive studies have demonstrated an increased blood oxygen level-dependent (BOLD) signal in homologous motor areas during action observation. One approach to demonstrating that this indicates the existence of mirror neurons in humans has been to employ functional (f)MRI adaptation to test whether the same population of neurons is active during both observation and execution conditions. Although a number of human studies have reported fMRI adaptation in these areas, a recent study has shown that macaque mirror neurons do not attenuate their firing rate with two repetitions. Here we investigated whether mirror neurons modulate their firing rate when monkeys observed the same repeated natural action multiple times. We recorded from 67 mirror neurons in area F5 of two macaque monkeys while they observed an experimenter perform a reach-to-grasp action on a small food reward using a precision grip. Although no changes were detectable for the first two repetitions, we show that both the firing rate and the latency at which mirror neurons discharged during observation were subtly modulated by the repetition of the observed action over 7–10 trials. Significant adaption was mostly found in the period immediately before the grasp was performed. We also found that the local field potential activity in F5 (beta-frequency range, 16–23 Hz), which is attenuated during action observation, also showed systematic changes with repeated observation. These LFP changes occurred well in advance of the mirror neuron adaptation. We conclude that macaque mirror neurons can show intra-modal adaptation, but whether this is related to fMRI adaptation of the BOLD signal requires further investigation.
NUP98 Fusion Oncoproteins Promote Aneuploidy by Attenuating the Mitotic Spindle Checkpoint
Authors: Salsi Valentina , Ferrari Silvia , Gorello Paolo , Fantini Sebastian , Chiavolelli Francesca , Mecucci Cristina , Zappavigna Vincenzo
Published: December 2013

NUP98 is a recurrent fusion partner in chromosome translocations that cause acute myelogenous leukemia. NUP98, a nucleoporin, and its interaction partner Rae1, have been implicated in the control of chromosome segregation, but their mechanistic contributions to tumorigenesis have been unclear. Here, we show that expression of NUP98 fusion oncoproteins causes mitotic spindle defects and chromosome missegregation, correlating with the capability of NUP98 fusions to cause premature securin degradation and slippage from an unsatisfied spindle assembly checkpoint (SAC). NUP98 fusions, unlike wild-type NUP98, were found to physically interact with the anaphase promoting complex/cyclosome (APC/C)Cdc20 and to displace the BubR1 SAC component, suggesting a possible mechanistic basis for their interference with SAC function. In addition, NUP98 oncoproteins displayed a prolonged half-life in cells. We found that NUP98 stability is controlled by a PEST sequence, absent in NUP98 oncoproteins, whose deletion reproduced the aberrant SAC-interfering activity of NUP98 oncoproteins. Together, our findings suggest that NUP98 oncoproteins predispose myeloid cells to oncogenic transformation or malignant progression by promoting whole chromosome instability. Cancer Res; 74(4); 1079–90. ©2013 AACR.
Oligodendrocyte Progenitor Cells Promote Neovascularization in Glioma by Disrupting the Blood–Brain Barrier
Authors: Huang Yujie , Hoffman Caitlin , Rajappa Prajwal , Kim Joon-Hyung , Hu Wenhuo , Huse Jason , Tang Zhongshu , Li Xuri , Weksler Babette , Bromberg Jacqueline , Lyden David C. , Greenfield Jeffrey P.
Published: December 2013

Enhanced platelet-derived growth factor (PDGF) signaling in glioma drives its development and progression. In this study, we define a unique role for stroma-derived PDGF signaling in maintaining tumor homeostasis within the glioma microenvironment. Large numbers of PDGF receptor-α (PDGFRα)–expressing stromal cells derived from oligodendrocytes progenitor cells (OPC) were discovered at the invasive front of high-grade gliomas, in which they exhibited a unique perivascular distribution. In PDGFRα-deficient host mice, in which orthotopic Gl261 tumors displayed reduced outgrowth, we found that tumor-associated blood vessels displayed smaller lumens and normalized vascular morphology, with tumors in host animals injected with the vascular imaging agent gadolinium also being enhanced less avidly by MRI. Notably, glioma-associated OPC promoted endothelial sprouting and tubule formation, in part by abrogating the inhibitory effect that perivascular astrocytes exert on vascular endothelial conjunctions. Stromal-derived PDGF-CC was crucial for the recruitment and activation of OPC, insofar as mice genetically deficient in PDGF-CC phenocopied the glioma/vascular defects observed in PDGFRα-deficient mice. Clinically, we showed that higher levels of PDGF-CC in glioma specimens were associated with more rapid disease recurrence and poorer overall survival. Our findings define a PDGFRα/PDGF-CC signaling axis within the glioma stromal microenvironment that contributes to vascular remodeling and aberrant tumor angiogenesis in the brain. Cancer Res; 74(4); 1011–21. ©2013 AACR.
Identification of Alternative Splicing Events Regulated by the Oncogenic Factor SRSF1 in Lung Cancer
Authors: de Miguel Fernando J. , Sharma Ravi D. , Pajares María J. , Montuenga Luis M. , Rubio Angel , Pio Ruben
Published: December 2013

Abnormal alternative splicing has been associated with cancer. Genome-wide microarrays can be used to detect differential splicing events. In this study, we have developed ExonPointer, an algorithm that uses data from exon and junction probes to identify annotated cassette exons. We used the algorithm to profile differential splicing events in lung adenocarcinoma A549 cells after downregulation of the oncogenic serine/arginine-rich splicing factor 1 (SRSF1). Data were generated using two different microarray platforms. The PCR-based validation rate of the top 20 ranked genes was 60% and 100%. Functional enrichment analyses found a substantial number of splicing events in genes related to RNA metabolism. These analyses also identified genes associated with cancer and developmental and hereditary disorders, as well as biologic processes such as cell division, apoptosis, and proliferation. Most of the top 20 ranked genes were validated in other adenocarcinoma and squamous cell lung cancer cells, with validation rates of 80% to 95% and 70% to 75%, respectively. Moreover, the analysis allowed us to identify four genes, ATP11C, IQCB1, TUBD1, and proline-rich coiled-coil 2C (PRRC2C), with a significantly different pattern of alternative splicing in primary non–small cell lung tumors compared with normal lung tissue. In the case of PRRC2C, SRSF1 downregulation led to the skipping of an exon overexpressed in primary lung tumors. Specific siRNA downregulation of the exon-containing variant significantly reduced cell growth. In conclusion, using a novel analytical tool, we have identified new splicing events regulated by the oncogenic splicing factor SRSF1 in lung cancer. Cancer Res; 74(4); 1105–15. ©2013 AACR.
A Preclinical Model of CD38-Pretargeted Radioimmunotherapy for Plasma Cell Malignancies
Authors: Green Damian J. , Orgun Nural N. , Jones Jon C. , Hylarides Mark D. , Pagel John M. , Hamlin Donald K. , Wilbur D.S. , Lin Yukang , Fisher Darrell R. , Kenoyer Aimee L. , Frayo Shani L. , Gopal Ajay K. , Orozco Johnnie J. , Gooley Theodore A. , Wood Brent L. , Bensinger William I. , Press Oliver W.
Published: December 2013

The vast majority of patients with plasma cell neoplasms die of progressive disease despite high response rates to novel agents. Malignant plasma cells are very radiosensitive, but the potential role of radioimmunotherapy (RIT) in the management of plasmacytomas and multiple myeloma has undergone only limited evaluation. Furthermore, CD38 has not been explored as a RIT target despite its uniform high expression on malignant plasma cells. In this report, both conventional RIT (directly radiolabeled antibody) and streptavidin–biotin pretargeted RIT (PRIT) directed against the CD38 antigen were assessed as approaches to deliver radiation doses sufficient for multiple myeloma cell eradication. PRIT demonstrated biodistributions that were markedly superior to conventional RIT. Tumor-to-blood ratios as high as 638:1 were seen 24 hours after PRIT, whereas ratios never exceeded 1:1 with conventional RIT. 90Yttrium absorbed dose estimates demonstrated excellent target-to-normal organ ratios (6:1 for the kidney, lung, liver; 10:1 for the whole body). Objective remissions were observed within 7 days in 100% of the mice treated with doses ranging from 800 to 1,200 μCi of anti-CD38 pretargeted 90Y–DOTA–biotin, including 100% complete remissions (no detectable tumor in treated mice compared with tumors that were 2,982% ± 2,834% of initial tumor volume in control animals) by day 23. Furthermore, 100% of animals bearing NCI-H929 multiple myeloma tumor xenografts treated with 800 μCi of anti-CD38 pretargeted 90Y–DOTA–biotin achieved long-term myeloma-free survival (>70 days) compared with none (0%) of the control animals. Cancer Res; 74(4); 1179–89. ©2013 AACR.
Curcumin Targets Breast Cancer Stem–like Cells with Microtentacles That Persist in Mammospheres and Promote Reattachment
Authors: Charpentier Monica S. , Whipple Rebecca A. , Vitolo Michele I. , Boggs Amanda E. , Slovic Jana , Thompson Keyata N. , Bhandary Lekhana , Martin Stuart S.
Published: December 2013

Cancer stem–like cells (CSC) and circulating tumor cells (CTC) have related properties associated with distant metastasis, but the mechanisms through which CSCs promote metastasis are unclear. In this study, we report that breast cancer cell lines with more stem-like properties display higher levels of microtentacles (McTN), a type of tubulin-based protrusion of the plasma cell membrane that forms on detached or suspended cells and aid in cell reattachment. We hypothesized that CSCs with large numbers of McTNs would more efficiently attach to distant tissues, promoting metastatic efficiency. The naturally occurring stem-like subpopulation of the human mammary epithelial (HMLE) cell line presents increased McTNs compared with its isogenic non–stem-like subpopulation. This increase was supported by elevated α-tubulin detyrosination and vimentin protein levels and organization. Increased McTNs in stem-like HMLEs promoted a faster initial reattachment of suspended cells that was inhibited by the tubulin-directed drug, colchicine, confirming a functional role for McTNs in stem cell reattachment. Moreover, live-cell confocal microscopy showed that McTNs persist in breast stem cell mammospheres as flexible, motile protrusions on the surface of the mammosphere. Although exposed to the environment, they also function as extensions between adjacent cells along cell–cell junctions. We found that treatment with the breast CSC-targeting compound curcumin rapidly extinguished McTN in breast CSC, preventing reattachment from suspension. Together, our results support a model in which breast CSCs with cytoskeletal alterations that promote McTNs can mediate attachment and metastasis but might be targeted by curcumin as an antimetastatic strategy. Cancer Res; 74(4); 1250–60. ©2013 AACR.
Tumor Suppressor Alterations Cooperate to Drive Aggressive Mesotheliomas with Enriched Cancer Stem Cells via a p53–miR-34a–c-Met Axis
Authors: Menges Craig W. , Kadariya Yuwaraj , Altomare Deborah , Talarchek Jacqueline , Neumann-Domer Erin , Wu Yue , Xiao Guang-Hui , Shapiro Irina M. , Kolev Vihren N. , Pachter Jonathan A. , Klein-Szanto Andres J. , Testa Joseph R.
Published: December 2013

Malignant mesothelioma is a highly aggressive, asbestos-related cancer frequently marked by mutations of both NF2 and CDKN2A. We demonstrate that germline knockout of one allele of each of these genes causes accelerated onset and progression of asbestos-induced malignant mesothelioma compared with asbestos-exposed Nf2+/− or wild-type mice. Ascites from some Nf2+/−;Cdkn2a+/− mice exhibited large tumor spheroids, and tail vein injections of malignant mesothelioma cells established from these mice, but not from Nf2+/− or wild-type mice, produced numerous tumors in the lung, suggesting increased metastatic potential of tumor cells from Nf2+/−;Cdkn2a+/− mice. Intraperitoneal injections of malignant mesothelioma cells derived from Nf2+/−;Cdkn2a+/− mice into severe combined immunodeficient mice produced tumors that penetrated the diaphragm and pleural cavity and harbored increased cancer stem cells (CSC). Malignant mesothelioma cells from Nf2+/−;Cdkn2a+/− mice stained positively for CSC markers and formed CSC spheroids in vitro more efficiently than counterparts from wild-type mice. Moreover, tumor cells from Nf2+/−;Cdkn2a+/− mice showed elevated c-Met expression/activation, which was partly dependent on p53-mediated regulation of miR-34a and required for tumor migration/invasiveness and maintenance of the CSC population. Collectively, these studies demonstrate in vivo that inactivation of Nf2 and Cdkn2a cooperate to drive the development of highly aggressive malignant mesotheliomas characterized by enhanced tumor spreading capability and the presence of a CSC population associated with p53/miR-34a–dependent activation of c-Met. These findings suggest that cooperativity between losses of Nf2 and Cdkn2a plays a fundamental role in driving the highly aggressive tumorigenic phenotype considered to be a hallmark of malignant mesothelioma. Cancer Res; 74(4); 1261–71. ©2013 AACR.
Apoptosis Signal–Regulating Kinase 1 Is a Novel Target Molecule for Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion
Authors: Toyama Kensuke , Koibuchi Nobutaka , Uekawa Ken , Hasegawa Yu , Kataoka Keiichiro , Katayama Tetsuji , Sueta Daisuke , Ma Ming Jie , Nakagawa Takashi , Yasuda Osamu , Tomimoto Hidekazu , Ichijo Hidenori , Ogawa Hisao , Kim-Mitsuyama Shokei
Published: December 2013

Objective—

There are currently no specific strategies for the treatment or prevention of vascular dementia. White matter lesions, a common pathology in cerebral small vessel disease, are a major cause of vascular dementia. We investigated whether apoptosis signal–regulating kinase 1 (ASK1) might be a key molecule in cerebral hypoperfusion, associated with blood–brain barrier breakdown and white matter lesions.

Approach and Results—

A mouse model of cognitive impairment was developed by inducing chronic cerebral hypoperfusion in white matter including the corpus callosum via bilateral common carotid artery stenosis (BCAS) surgery. BCAS-induced white matter lesions caused cognitive decline in C57BL/6J (wild-type) mice but not in ASK1-deficient (ASK1
−/−
) mice. Phosphorylated ASK1 increased in wild-type mouse brains, and phosphorylated p38 and tumor necrosis factor-α expression increased in corpus callosum cerebral endothelial cells after BCAS in wild-type mice but not in ASK1
−/−
mice. BCAS decreased claudin-5 expression and disrupted blood–brain barrier in the corpus callosum of wild-type but not ASK1
−/−
mice. Cerebral nitrotyrosine was increased in wild-type and ASK1
−/−
BCAS mice. Cerebral phosphorylated ASK1 did not increase in wild-type mice treated with NADPH-oxidase inhibitor. A p38 inhibitor and NADPH-oxidase inhibitor mimicked the protective effect of ASK1 deficiency against cognitive impairment. Specific ASK1 inhibitor prevented cognitive decline in BCAS mice. In vitro oxygen-glucose deprivation and tumor necrosis factor-α stimulation caused the disruption of endothelial tight junctions from wild-type mice but not ASK1
−/−
mice.

Conclusions—

Oxidative stress-ASK1-p38 cascade plays a role in the pathogenesis of cognitive impairment, through blood–brain barrier breakdown via the disruption of endothelial tight junctions. ASK1 might be a promising therapeutic target for chronic cerebral hypoperfusion–induced cognitive impairment.
Alpha-Chlorofatty Acid Accumulates in Activated Monocytes and Causes Apoptosis Through Reactive Oxygen Species Production and Endoplasmic Reticulum Stress
Authors: Wang Wen-yi , Albert Carolyn J. , Ford David A.
Published: December 2013

Objective—

Myeloperoxidase-enriched monocytes play important roles in inflammatory disease, such as atherosclerosis. We previously demonstrated that α-chlorofatty aldehydes are produced as a result of plasmalogen targeting by myeloperoxidase-derived hypochlorous acid in activated monocytes. Here, we show α-chlorofatty acid (α-ClFA), a stable metabolite of α-chlorofatty aldehydes, accumulates in activated monocytes and mediates the molecular effects of α-ClFA on monocytes/macrophages.

Approach and Results—

Liquid chromatography-mass spectrometry revealed that α-ClFA is elevated 5-fold in phorbol myristate–stimulated human monocytes rising to ≈20 μmol/L when compared with unstimulated cells. Using human THP-1 monocytes and RAW 264.7 cells as in vitro models, we tested the hypothesis that α-ClFA is a cell death mediator that could potentially participate in pathophysiological roles of monocytes in diseases, such as atherosclerosis. Indeed, 2-chlorohexadecanoic acid, the 16-carbon molecular species of α-ClFA, caused significant apoptosis of primary monocytes. Similarly, 2-chlorohexadecanoic acid also caused apoptosis in THP-1 human monocytes and RAW 264.7 mouse macrophages as determined by annexin V-propidium iodide staining and terminal deoxynucleotidyl transferase dUTP nick end labeling staining, respectively. 2-Chlorohexadecanoic acid treatment also increased caspase-3 activity and poly (ADP-ribose) polymerase cleavage in THP-1 cells. 2-Chlorohexadecanoic acid likely elicits apoptosis by increasing both reactive oxygen species production and endoplasmic reticulum stress because antioxidants and CCAAT/enhancer-binding protein homologous protein block such induced cell apoptosis.

Conclusions—

The stable chlorinated lipid, α-ClFA, accumulates in activated primary human monocytes and elicits monocyte apoptosis through increased reactive oxygen species production and endoplasmic reticulum stress, providing a new insight into chlorinated lipids and monocytes in inflammatory disease.
Remote Ischemic Preconditioning Preserves Mitochondrial Function and Influences Myocardial MicroRNA Expression in Atrial Myocardium During Coronary Bypass Surgery
Authors: Slagsvold Katrine Hordnes , Rognmo Øivind , Høydal Morten , Wisløff Ulrik , Wahba Alexander
Published: December 2013

Rationale:

Remote ischemic preconditioning (RIPC) has been suggested to induce cardioprotection during cardiac surgery. Maintaining proper atrial function is imperative in preventing arrhythmia and thrombus formation. Mitochondria have been proposed as key targets in conveying RIPC mechanisms and effects. MicroRNA (miR) is emerging as an important regulator of mitochondrial function, arrhythmia, and protection from ischemia and reperfusion.

Objective:

This study aimed to evaluate the effect of RIPC on mitochondrial respiration and miR expression in human atrial tissue.

Methods and Results:

Sixty patients undergoing coronary artery bypass graft surgery were randomized to RIPC (n=30) or control (n=30). RIPC was performed preoperatively by inflating a blood pressure cuff on the upper arm to 200 mm Hg for 3×5 minutes, with 5 minutes reperfusion intervals. Biopsies were obtained from the right atrial appendage before and after aortic cross-clamping. Mitochondrial respiration was measured in situ and miR assessed by commercial miR array and quantitative reverse transcription polymerase chain reaction. Postoperative atrial fibrillation occurrence was monitored by biotelemetry. Maximal mitochondrial respiration was preserved throughout surgery after RIPC but significantly reduced (−28%;
P
<0.05) after aortic cross-clamping in control. Incidence of postoperative atrial fibrillation was lower after RIPC versus control (14% versus 50%;
P
<0.01). Myocardial expression of miR-133a and miR-133b increased after aortic cross-clamping in both RIPC and control, whereas miR-1 was upregulated in control only. MiR-338-3p expression was higher in RIPC versus control after aortic cross-clamping.

Conclusions:

RIPC preserves mitochondrial respiration and prevents upregulation of miR-1 in the right atrium during coronary artery bypass graft.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01308138