bluuebunny/crossref_metadata_2025 huggingface dataset:
EMERGENCE OF RANDOMNESS FROM CHAOS
Authors: LOZI R.
Published: February 2012

In systems theory and science, emergence is the way complex systems and patterns arise out of a multiplicity of relatively simple interactions. Emergence is central to the theories of integrative levels and of complex systems [Aziz-Alaoui & Bertelle, 2009]. In this paper, we use the emergent property of the ultra weak multidimensional coupling of p 1-dimensional dynamical chaotic systems which leads from chaos to randomness.

Generation of random or pseudorandom numbers, nowadays, is a key feature of industrial mathematics. Pseudorandom or chaotic numbers are used in many areas of contemporary technology such as modern communication systems and engineering applications. More and more European or US patents using discrete mappings for this purpose are obtained by researchers of discrete dynamical systems [Petersen & Sorensen, 2007; Ruggiero et al., 2006]. Efficient Chaotic Pseudo Random Number Generators (CPRNG) have been recently introduced. They use the ultra weak multidimensional coupling of p 1-dimensional dynamical systems which preserve the chaotic properties of the continuous models in numerical experiments. Together with chaotic sampling and mixing processes, ultra weak coupling leads to families of (CPRNG) which are noteworthy [Hénaff et al., 2009a, 2009b, 2009c, 2010].

In this paper we improve again these families using a double threshold chaotic sampling instead of a single one.

We analyze numerically the properties of these new families and underline their very high qualities and usefulness as CPRNG when very long series are computed. Moreover, a determining property of such improved CPRNG is the high number of parameters used and the high sensitivity to the parameters value which allows choosing it as cipher-keys. It is why we call these families multiparameter chaotic pseudo-random number generators (M-p CPRNG).
COMPLEX DYNAMICS OF ELEMENTARY CELLULAR AUTOMATA EMERGING FROM CHAOTIC RULES
Authors: MARTÍNEZ GENARO J. , ADAMATZKY ANDREW , ALONSO-SANZ RAMON
Published: February 2012

We show techniques of analyzing complex dynamics of cellular automata (CA) with chaotic behavior. CA are well-known computational substrates for studying emergent collective behavior, complexity, randomness and interaction between order and chaotic systems. A number of attempts have been made to classify CA functions on their space-time dynamics and to predict the behavior of any given function. Examples include mechanical computation, λ and Z-parameters, mean field theory, differential equations and number conserving features. We aim to classify CA based on their behavior when they act in a historical mode, i.e. as CA with memory. We demonstrate that cell-state transition rules enriched with memory quickly transform a chaotic system converging to a complex global behavior from almost any initial condition. Thus, just in few steps we can select chaotic rules without exhaustive computational experiments or recurring to additional parameters. We provide an analysis of well-known chaotic functions in one-dimensional CA, and decompose dynamics of the automata using majority memory exploring glider dynamics and reactions.
QUANTIFYING CHANGES IN THE SPATIAL STRUCTURE OF TRABECULAR BONE
Authors: MARWAN NORBERT , BELLER GISE , FELSENBERG DIETER , SAPARIN PETER , KURTHS JÜRGEN
Published: February 2012

We apply recently introduced measures of complexity for the structural quantification of distal tibial bone. For the first time, we are able to investigate the temporal structural alteration of trabecular bone. Based on four patients, we show how the bone may alter due to temporal immobilization.
DYNAMICS UNDERLYING PATIENT-VENTILATOR INTERACTIONS DURING NOCTURNAL NONINVASIVE VENTILATION
Authors: NAECK R. , BOUNOIARE D. , FREITAS U. S. , RABARIMANANTSOA H. , PORTMANN A. , PORTIER F. , CUVELIER A. , MUIR J.-F. , LETELLIER C.
Published: February 2012

Noninvasive ventilation is a common procedure for managing patients having chronic respiratory failure. The success of this ventilatory assistance is often linked with patient's tolerance that is known to be related to the quality of the synchronization between patient's spontaneous breathing cycles and ventilatory cycles delivered by the ventilator. Thirty-four sleep sessions (more than 5000 ventilatory cycles each) were automatically investigated using a specific algorithm processing airflow and pressure time series. Four groups of patients were defined according to the interplay between asynchrony events and leaks. Different mechanisms that depend on sleep stages were thus evidenced. A Shannon entropy was also proposed as a new sleep fragmentation quantification methodology.
PREVENTION OF INSTABILITY OF THE PROXIMAL END OF THE RADIUS AFTER RADIAL HEAD RESECTION USING AN ANCONEUS MUSCLE FLAP
Authors: Nishida Kinya , Iwasaki Norimasa , Funakoshi Tadanao , Motomiya Makoto , Minami Akio
Published: February 2012

Resection of the radial head frequently causes instability of the proximal end of the radius. To prevent this instability, we performed a stabilization technique using an anconeus muscle flap. Since 2003, six patients with radiocapitellar joint dysfunction have been treated with radial head resection combined with stabilizing its proximal end using an anconeus muscle flap. At a mean follow-up of 51 months, all patients were free from elbow pain and the mean Mayo Elbow Performance Score and the Disabilities of the Arm, Shoulder and Hand score significantly improved. Radiographic findings showed no apparent instability of the proximal radius. The anconeus is useful as a reliable muscle flap for preventing instability of the proximal radius after a radial head resection. This procedure does not require any microvascular techniques and makes it possible to apply a pedicled muscle flap using a relatively simple technique without any considerable risks of elbow dysfunction.
OPEN EXTENSOR TENDON INJURIES: AN EPIDEMIOLOGIC STUDY
Authors: Patillo Dominic , Rayan Ghazi M.
Published: February 2012

Purpose: To report the epidemiology, mechanism, anatomical location, distribution, and severity of open extensor tendon injuries in the digits, hand, and forearm as well as the frequency of associated injuries to surrounding bone and soft tissue.

Methods: Retrospective chart review was conducted for patients who had operative repair of open digital extensor tendon injuries in all zones within an 11-year period. Data was grouped according to patient characteristics, zone of injury, mechanism of injury, and presence of associated injury. Statistical analysis was used to determine the presence of relevant associations.

Results: Eighty-six patients with 125 severed tendons and 105 injured digits were available for chart reviews. Patients were predominantly males (83%) with a mean age of 34.2 years and the dominant extremity was most often injured (60%). The thumb was the most commonly injured (25.7%), followed by middle finger (24.8), whereas small finger was least affected (10.5%). Sharp laceration was the most common mechanism of injury (60%), and most of these occurred at or proximal to the metacarpophalangeal joints. Most saw injuries occurred distal to the metacarpophalangeal joint. Zone V was the most commonly affected in the fingers (27%) while zone VT was the most commonly affected in the thumb (69%). Associated injuries to bone and soft tissue occurred in 46.7% of all injuries with saw and crush/avulsions being predictive of fractures and damage to the underlying joint capsule.

Conclusions: The extensor mechanism is anatomically complex, and open injuries to the dorsum of the hand, wrist, and forearm, especially of crushing nature and those inflicted by saws, must be thoroughly evaluated. Associated injuries should be ruled out in order to customize surgical treatment and optimize outcome.
THE CARPAL STRETCH TEST AT THE RHEUMATOID WRIST
Authors: Shimizu Hiroyuki , Beppu Moroe , Matsusita Kazuhiko , Arai Takeshi , Yoshida Noriyuki
Published: February 2012

The purpose of this study was to evaluate the radiographic changes of the carpus for rheumatoid wrists in patients who underwent the Sauvé-Kapandji procedure by examining the clinical results and comparing pre- and postoperative radiographic measurements. We studied 43 wrists in 37 patients who showed vertical laxity in the radiocarpal and midcarpal joint on preoperative carpal stretch test. Pain was improved in all patients and the forearm rotation angles of the wrist were significantly improved after the operation. The carpal collapse ratio was significantly reduced after the operation. The carpal collapse reduction rate was significantly greater in the group with than that in the group without midcarpal joint vertical laxity on the carpal stretch test. Although the Sauvé-Kapandji procedure was not sufficiently effective in preventing carpal collapse, it did have a protective effect against ulnar carpal shift. The results of our study showed that vertical laxity of the midcarpal joint was the risk factor of the carpal collapse after Sauvé-Kapandji procedure.
THE CURRENT PRACTICE OF THE MANAGEMENT OF LITTLE FINGER METACARPAL FRACTURES — A REVIEW OF THE LITERATURE AND RESULTS OF A SURVEY CONDUCTED AMONG UPPER LIMB SURGEONS IN THE UNITED KINGDOM
Authors: Sahu A. , Gujral S. S. , Batra S. , Mills S. P. , Srinivasan M. S.
Published: February 2012

Little finger metacarpal fractures are the most common type of metacarpal fractures and the treatment is quite variable as it is a multifactorial entity comprised of subcapital, metacarpal shaft and base fractures. These fractures are common presentations in the fracture clinics and the general orthopaedic surgeons treat them until a complex case warrants specific decision making by a hand surgeon. The management of many of these fractures is still a matter of debate and differ widely in the various parts of the United Kingdom. The aim of this study was to investigate the current practice of little finger metacarpal fractures among upper limb surgeons in the UK. We conducted an online survey among 278 upper limb orthopaedic specialist surgeons throughout the UK. Our response rate was 58%. There are various factors which dictate the treatment as suggested by these respondent upper limb consultants. For example, for fifth metacarpal neck fractures, it was generally recognised that 43% of upper limb surgeons prefer neighbour strapping alone for non-operative management of little finger metacarpal fractures. For little finger metacarpal shaft fractures, 39.3% of surgeons suggested that they would contemplate intervention, i.e. manipulation under anaesthesia/surgery if beyond 30° of volar angulation is present. For little finger metacarpal neck fractures, 33.7% would only consider surgical intervention beyond 60° of volar angulation. 91.6% of upper limb specialists agreed that they would operate on little finger metacarpal base fractures only if it was a fracture dislocation, while 71.8% suggested that they would proceed to operate on even a pure dislocation. We have illustrated the various permutations and combinations of these fractures with the results of our survey in this article in detail. The vast majority of metacarpal bone fractures are stable and treated conservatively. The different types of injury patterns must be recognised by the orthopaedic surgeons and appropriate treatment then should be executed to serve the patient optimally in due course.
CUBITAL TUNNEL SYNDROME ASSOCIATED WITH ARTHROGRYPOSIS: A CASE REPORT
Authors: Motomiya Makoto , Iwasaki Norimasa , Minami Akio
Published: February 2012

Arthrogryposis is a syndrome of multiple joint contracture and subluxation that is present at birth and is characterized by a nonprogressive disorder. Patients with lack of active elbow motion show the typical elbow motion with passive assistance, such as the trunk-sway and cross-arm techniques. We describe our experience with the treatment of an arthrogryposis patient with cubital tunnel syndrome caused by the passive elbow motion. The ulnar nerve was entrapped by a thick fibrous band at the cubital tunnel, and simple decompression of the ulnar nerve brought the patient a good recovery from the palsy.
RADIAL AND VOLAR PERILUNATE TRANS-SCAPHOID FRACTURE DISLOCATION: A CASE REPORT
Authors: Nishiyama Yuichiro , Sato Kazuki , Nakamura Toshiyasu , Okazaki Masato , Toyama Yoshiaki , Ikegami Hiroyasu
Published: February 2012

A case of radial and volar perilunate trans-scaphoid fracture dislocation in which the proximal fragment of the scaphoid was dislocated dorsally is presented.
LOCKING OF THE PROXIMAL INTERPHALANGEAL JOINT OF THE RING FINGER DUE TO THE NEGLECTED FLEXOR DIGITORUM PROFUNDUS AVULSION
Authors: Hattori Yasunori , Doi Kazuteru , Sakamoto Soutetsu , Dodakundi Chaitanya
Published: February 2012

We report an unusual case of proximal interphalangeal joint locking of the ring finger due to the neglected flexor digitorum profundus avulsion. Although rare, it should be noted that locking is a potential complication after this injury.
A SWOLLEN MIDDLE FINGER IN A MIDDLE-AGED FARMER
Authors: Basu Somprakas , Bhadani Shilpi , Shukla Vijay Kumar
Published: February 2012

Hand tumors are not common and a swollen finger poses considerable diagnostic dilemma. We present a case of a middle-aged farmer who had presented with a painless swelling of the middle finger of the right hand without any neurovascular deficit or evidence of metastasis. An X-ray of the finger showed cortical expansion and bony erosion of the proximal phalanx. A fine needle aspiration cytological examination was inconclusive. He underwent a digit amputation in view of subsequent morbidity and chances of recurrence following local excision. Biopsy proved it to be a giant cell tumor of the proximal phalanx. Following six months of treatment he is doing well. We herein highlight an unusual tumor of the finger and its diagnostic and treatment challenges.
NAIL DYSTROPHY IN PSORIATIC ARTHRITIS PRESENTING AS NAIL ONYCHOMYCOSIS: A CASE REPORT
Authors: Kim Joon Yub , Baek Goo Hyun , Gong Hyun Sik
Published: February 2012

Dystrophic nail changes without a skin lesion is a rare form of psoriasis. We describe a patient that presented with a chronic nail onychomycosis and a destructive thumb interphalangeal joint which was initially considered as onychomycotic joint infection, and was later diagnosed as having dystrophic nail changes in psoriatic arthritis and coexistent onychomycosis. The nail changes were completely normalized after methotrexate treatment.
COMBINATION V-Y ADVANCEMENT FLAP AND COMPOSITE GRAFT FOR RECONSTRUCTION OF AN AMPUTATED FINGERTIP
Authors: Lee Sang-Mok , Rahman M. Fazlur , Thirkannad Sunil
Published: February 2012

Fingertip amputations can lead to both functional and aesthetic problems. We present the results of our preferred technique to address fingertip amputations in zone 1 and zone 2 which have been deemed non-replantable by microsurgery. It is based on the "reposition technique" described by Dubert et al. in 19971and the free perionychial graft technique suggested by Netscher and Meade in 1999.2The technique that we prefer is best described as a combination of an advancement flap and a composite graft. So far seven patients have been treated with this method and our results have been satisfactory in all of them. It is a simple and quick technique that does not require advanced skills and can be done by a well-trained resident or fellow. It allows preservation of finger length, retains the nail and is functionally and aesthetically pleasing.
A DFT STUDY OF CO MIGRATORY INSERTION REACTIONS WITH A NEW TYPE OF GROUP 10 METAL-ALKYL AND METAL-ALKOXIDE BONDS
Authors: BI SIWEI , ZHAO JUNFENG , FAN WEI , LI PING
Published: February 2012

The CO migratory insertion into M–O and M–C bonds of the new model (PMe3)2M(η2 – CH2CH2O) ( M = Ni , Pd and Pt ) (model (d)) proposed in this work has been studied with the aid of density functional theory (DFT) calculations. It is found (1) when M = Ni , CO migratory insertion into Ni–C is thermodynamically and kinetically favored, and (2) when M = Pd and Pt , the insertion into M–O bond via a one-step process is preferred. Further investigation on CO migratory insertion using Pt(PMe3)2(C7H10O) (R′-Pt) derived from the experimental compound Pt(PEt3)2(C7H10O) gives the same conclusions as model (d) with M = Pt . Results obtained from the reaction of model (d) ( M = Pt ) with CO are consistent with the experimental observation that CO prefers to insert into Pt–O bond of Pt(PEt3)2(C7H10O) .
STEREODYNAMICS AND ISOTOPE EFFECTS FOR THE REACTION N + NH → N2 + H
Authors: CHEN YINGYING , ZHAO MEIYU
Published: February 2012

Quasi-Classical Trajectory (QCT) calculations have been carried out to study the stereodynamics of the reactions N + NH → N 2 + H and isotopic effects on the product polarization at collision energies of 10.0 kcal/mol and 25.0 kcal/mol which proceed on the Double-Many-Body-Expansion (DMBE) potential energy surface. The distribution of dihedral angle P(ϕr), and the distribution of angle between k and j′, P(θr) are discussed in detail. Furthermore, four generalized polarization dependent differential cross sections (PDDCSs) (2π/σ)(dσ00/dω), (2π/σ)(dσ20/dω), (2π/;σ)(dσ22+/dω), and (2π/σ)(dσ21 -∕dω) are presented. The results reveal that isotope effect plays an important role for P(ϕr) and P(θr) distribution, and the PDDCSs exhibit similar collision energy dependency relationship at low and high collision energies.
THEORETICAL AND EXPERIMENTAL STUDY ON THE REGIOSELECTIVITY OF ACRYLONITRILE AND METHYLMETHACRYLATE 1,3-DIPOLAR CYCLOADDITION TO SOME NITRILIMINES
Authors: MOEINPOUR F. , BAKAVOLI M. , DAVOODNIA A. , MORSALI A.
Published: February 2012

1,3-dipolar cycloaddition between acrylonitrile and methylmethacrylate with two N-(4-bromophenyl)-C-(4-substituted) nitrilimines which were generated in situ afforded the new pyrazoles. The regioselectivity and reactivity of these reactions has been investigated on the basis of density functional theory (DFT)-based reactivity indexes and activation energy calculations. The theoretical 13C NMR chemical shifts of the cycloadducts which were obtained by GIAO method were comparable with the observed values.
THE RATE CONSTANT OF THE O(3P) + HCl → OH + Cl REACTION WITHIN QUANTUM INSTANTON APPROXIMATION
Authors: BUCHOWIECKI MARCIN
Published: February 2012

Temperature dependence of the rate constant of the O (3 P ) + HCl → OH + Cl reaction was calculated for 200–700 K range within the quantum instanton approximation using the 3A″ potential energy surface. Curvature of the Arrhenius plot arising from quantum effects in the hydrogen exchange reaction was observed. Results of the present method were found to significantly improve upon those obtained within the ICVT/μOMT method. The errors pertaining to the present method were estimated.
DENSITY FUNCTIONAL THEORY STUDIES OF CHARGED, COPPER-DOPED, SMALL SILICON CLUSTERS, ${\rm CuSi}_{n}^{+}/{\rm CuSi}_{n}^{-}$ (n = 1–7)
Authors: LI GUOLIANG , MA WENLIANG , GAO AIMEI , CHEN HONGYU , FINLOW DAVID , LI QIAN-SHU
Published: February 2012

The structures and stabilities of charged, copper-doped, small silicon clusters [Formula: see text] (n = 1–7) have been systematically investigated using the density functional theory method at the B3LYP/6-311+G* level. For comparison, the geometries of neutral CuSi n clusters were also optimized at the same level, although most of them have been reported previously [see Xiao CY, Abraham A, Quinn R, Hagelberg F, Comparative study on the interaction of scandium and copper atoms with small silicon clusters, J Phys Chem A106:11380, 2002; Liu X, Zhao GF, Guo LJ, Wang XW, Zhang J, Jing Q, Luo YH, First-principle studies of the geometries and electronic properties of Cu m Si n (2 ≤ m + n ≤ 7) clusters, Chin Phys16:3359, 2007]. Our results for the ground state structures of neutral CuSi n clusters agree well with those of Liu et al. and Xiao et al. except for CuSi3 and CuSi7 . Removing or adding an electron greatly changes some ground state structures, i.e. for [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text]; others are almost unchanged, e.g. [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text]. The ground states of ionic [Formula: see text] are all singlet, except for the smaller CuSi- and [Formula: see text]. Based on the optimized geometries, various energetic properties, including binding energies, second-order difference energies, the highest occupied molecular orbit and the lowest unoccupied molecular orbital (HOMO–LUMO) energy gaps, ionization potential and electron affinities, were calculated for the most stable isomers of [Formula: see text]. All the results indicate that anionic [Formula: see text] and cationic [Formula: see text] clusters are relatively stable. The higher stability of the latter has been confirmed by Beck's observations.
ELECTRON TRANSFER MAKES D3h (78:5) CAGE EASY TO FORM M2@C78(M = La, Ce): A RELATIVISTIC DENSITY-FUNCTIONAL THEORY STUDY
Authors: HAO CE , LI HONGJIANG , JIA GUORONG , LI SHENMIN , QIU JIESHAN
Published: February 2012

Applying relativistic density functional theory to isomers of C 78 and M 2@ C 78( M = La , Ce ), we calculate and analyze the relative energies and HOMO–LUMO gaps of neutral and hexaanion ( -6 charged) C 78 isomers. Our results indicate that the [Formula: see text] (5) isomer is the most stable, and it illustrate that electron transfer plays an important role in controlling the stability of endohedral metallofullerenes. We also calculate the electronic structures of there neutral isomers, and based on their LUMO + 2 and LUMO + 3 gaps, we explain why it is easier to encage two metal atoms in D3h′ (78:5). To further elucidate this issue, we theoretically characterize M 2@ C 78( M = La , Ce ) and compare the relative energies and the HOMO–LUMO gap of the two isomers M 2@ C 78 (4) and the M 2@ C 78 (5) ( M = La , Ce ). The results indicate that M 2@ C 78 (5) is more stable than M 2@ C 78 (4). Furthermore, the good agreement between the experimental and computed 13C NMR chemical shift of the isomer M 2@ C 78 (5) provided strong evidence that M 2@ C 78 forms a D3h′ (78:5) cage.
THE INVESTIGATION OF SECOND-ORDER NONLINEAR OPTICAL PROPERTIES OF P-NITROPHENYLAZOANILINE: SECOND HARMONIC GENERATION AND AB INITIO COMPUTATIONS
Authors: KARAKAŞ ASLI , KOÇ ZİYA ERDEM , FRIDRICHOVÁ MICHAELA , NĚMEC PETR , KROUPA JAN
Published: February 2012

p-nitrophenylazoaniline (1) belongs to the family of compounds with conjugated bonds and delocalized π-electrons, structurally similar to the well known push-pull compound Disperse Red 1 (DR1).1 Due to the assembly of the molecule, nonlinear optical (NLO) properties are expectable and can be more or less accurately predicted. To estimate the potential for second-order NLO properties, the electric dipole moment (μ), dispersion-free dipole polarizabilities (α) and first hyperpolarizabilities (β) have been determined by density functional theory (DFT) quantum chemical calculations at B3LYP/ 6-311 + G(d, p) level. According to the computation results, the synthesized compound exhibits non-zero β values and it might have second-order NLO behavior. Title compound has been synthesized and characterized by FT-IR, 1H-NMR and UV-Vis spectroscopies. The maximum one-photon absorption (OPA) wavelengths were estimated to be shorter than 450 nm by quantum mechanical computations using the configuration interaction (CI) method. The same result was achieved by UV-Vis spectra measurements, whereas the compound exhibited good optical transparency to the visible light. Quantitative measurements of second harmonic generation (SHG) at 800 nm and 1064 nm have been performed. The relative efficiency comparable with that of KDP (kalium diphosphate) has been observed with the exciting wavelength of 1064 nm, while the other wavelength led to strong absorption of produced light by the sample. In the following more detailed study on frequency-dependent first hyperpolarizabilities using time-dependent Hartree–Fock (TDHF) method have been computed at the wavelengths used in SHG measurements.
Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption
Authors: Fox Raymond G. , Magness Scott , Kujoth Gregory C. , Prolla Tomas A. , Maeda Nobuyo
Published: February 2012

Changes in intestinal absorption of nutrients are important aspects of the aging process. To address this issue, we investigated the impact of accelerated mitochondrial DNA mutations on the stem/progenitor cells in the crypts of Lieberkühn in mice homozygous for a mitochondrial DNA polymerase gamma mutation, PolgD257A, that exhibit accelerated aging phenotype. As early as 3–7 mo of age, the small intestine was significantly enlarged in the PolgD257A mice. The crypts of the PolgD257A mice contained 20% more cells than those of their wild-type littermates and exhibited a 10-fold increase in cellular apoptosis primarily in the stem/progenitor cell zones. Actively dividing cells were proportionally increased, yet a significantly smaller proportion of cells was in the S phase of the cell cycle. Stem cell-derived organoids from PolgD257A mice failed to develop fully in culture and exhibited fewer crypt units, indicating an impact of the mutation on the intestinal epithelial stem/progenitor cell maintenance. In addition, epithelial cell migration along the crypt-villus axis was slowed and less organized, and the ATP content in the villi was significantly reduced. On a high-fat, high-carbohydrate diet, PolgD257A mice showed significantly restricted absorption of excess lipids accompanied by an increase in fecal steatocrits. We conclude that the PolgD257A mutation causes cell cycle dysregulation in the crypts leading to the age-associated changes in the morphology of the small intestine and contributes to the restricted absorption of dietary lipids.
Direct methylation of FXR by Set7/9, a lysine methyltransferase, regulates the expression of FXR target genes
Authors: Balasubramaniyan Natarajan , Ananthanarayanan Meena , Suchy Frederick J.
Published: February 2012

The farnesoid X receptor (FXR) is a ligand (bile acid)-dependent nuclear receptor that regulates target genes involved in every aspect of bile acid homeostasis. Upon binding of ligand, FXR recruits an array of coactivators and associated proteins, some of which have intrinsic enzymatic activity that modify histones or even components of the transcriptional complex. In this study, we show chromatin occupancy by the Set7/9 methyltransferase at the FXR response element (FXRE) and direct methylation of FXR in vivo and in vitro at lysine 206. siRNA depletion of Set7/9 in the Huh-7 liver cell line decreased endogenous mRNAs of the FXR target genes, the short heterodimer partner (SHP) and bile salt export pump (BSEP). Mutation of the methylation site at K206 of FXR to an arginine prevented methylation by Set7/9. A pan-methyllysine antibody recognized the wild-type FXR but not the K206R mutant form. An electromobility shift assay showed that methylation by Set7/9 enhanced binding of FXR/retinoic X receptor-α to the FXRE. Interaction between hinge domain of FXR (containing K206) and Set7/9 was confirmed by coimmunoprecipitation, GST pull down, and mammalian two-hybrid experiments. Set7/9 overexpression in Huh-7 cells significantly enhanced transactivation of the SHP and BSEP promoters in a ligand-dependent fashion by wild-type FXR but not the K206R mutant FXR. A Set7/9 mutant deficient in methyltransferase activity was also not effective in increasing transactivation of the BSEP promoter. These studies demonstrate that posttranslational methylation of FXR by Set7/9 contributes to the transcriptional activation of FXR-target genes.
Chloride in airway smooth muscle: the ignored anion no longer?
Authors: Gallos George , Yim Peter , Emala Charles W.
Published: February 2012

This Perspectives accompanies an Editorial Focus that summarizes new developments concerning the role of chloride in airway smooth muscle physiology. We provide several observations and mechanistic insights to reconcile recent experimental evidence with existing paradigms concerning chloride channel-mediated effects on airway smooth muscle tone. In addition, we highlight the potentially complex and dynamic nature that chloride currents and membrane potential have on calcium handling and airway smooth muscle contractility.
Effect of rowing ergometry and oral volume loading on cardiovascular structure and function during bed rest
Authors: Hastings Jeffrey L. , Krainski Felix , Snell Peter G. , Pacini Eric L. , Jain Manish , Bhella Paul S. , Shibata Shigeki , Fu Qi , Palmer M. Dean , Levine Benjamin D.
Published: February 2012

This study examined the effectiveness of a short-duration but high-intensity exercise countermeasure in combination with a novel oral volume load in preventing bed rest deconditioning and orthostatic intolerance. Bed rest reduces work capacity and orthostatic tolerance due in part to cardiac atrophy and decreased stroke volume. Twenty seven healthy subjects completed 5 wk of −6 degree head down bed rest. Eighteen were randomized to daily rowing ergometry and biweekly strength training while nine remained sedentary. Measurements included cardiac mass, invasive pressure-volume relations, maximal upright exercise capacity, and orthostatic tolerance. Before post-bed rest orthostatic tolerance and exercise testing, nine exercise subjects were given 2 days of fludrocortisone and increased salt. Sedentary bed rest led to cardiac atrophy (125 ± 23 vs. 115 ± 20 g; P < 0.001); however, exercise preserved cardiac mass (128 ± 38 vs. 137 ± 34 g; P = 0.002). Exercise training preserved left ventricular chamber compliance, whereas sedentary bed rest increased stiffness (180 ± 170%, P = 0.032). Orthostatic tolerance was preserved only when exercise was combined with volume loading (−10 ± 22%, P = 0.169) but not with exercise (−14 ± 43%, P = 0.047) or sedentary bed rest (−24 ± 26%, P = 0.035) alone. Rowing and supplemental strength training prevent cardiovascular deconditioning during prolonged bed rest. When combined with an oral volume load, orthostatic tolerance is also preserved. This combined countermeasure may be an ideal strategy for prolonged spaceflight, or patients with orthostatic intolerance.
Akt and MAPK signaling mediate pregnancy-induced cardiac adaptation
Authors: Chung Eunhee , Yeung Fan , Leinwand Leslie A.
Published: February 2012

Although the signaling pathways underlying exercise-induced cardiac adaptation have been extensively studied, little is known about the molecular mechanisms that result in the response of the heart to pregnancy. The objective of this study was to define the morphological, functional, and gene expression patterns that define the hearts of pregnant mice, and to identify the signaling pathways that mediate this response. Mice were divided into three groups: nonpregnant diestrus control, midpregnancy, and late pregnancy. Both time points of pregnancy were associated with significant cardiac hypertrophy. The prosurvival signaling cascades of Akt and ERK1/2 were activated in the hearts of pregnant mice, while the stress kinase, p38, was decreased. Given the activation of Akt in pregnancy and its known role in cardiac hypertrophy, the hypertrophic response to pregnancy was tested in mice expressing a cardiac-specific activated (myristoylated) form of Akt (myrAkt) or a cardiac-specific constitutively active (antipathologic hypertrophic) form of its downstream target, glycogen synthase kinase 3β (caGSK3β). The pregnancy-induced hypertrophic responses of hearts from these mice were significantly attenuated. Finally, we tested whether pregnancy-associated sex hormones could induce hypertrophy and alter signaling pathways in isolated neonatal rat ventricular myocytes (NRVMs). In fact, progesterone, but not estradiol treatment increased NRVM cell size via phosphorylation of ERK1/2. Inhibition of MEK1 effectively blocked progesterone-induced cellular hypertrophy. Taken together, our study demonstrates that pregnancy-induced cardiac hypertrophy is mediated by activation of Akt and ERK1/2 pathways.
EMG activity in hyoid muscles during pig suckling
Authors: Thexton A. J. , Crompton A. W. , German R. Z.
Published: February 2012

Infant suckling is a complex behavior that includes cycles of rhythmic sucking as well as intermittent swallows. This behavior has three cycle types: 1) suck cycles, when milk is obtained from the teat and moved posteriorly into the valleculae in the oropharynx; 2) suck-swallow cycles, which include both a rhythmic suck and a pharyngeal swallow, where milk is moved out of the valleculae, past the larynx, and into the esophagus; and 3) postswallow suck cycles, immediately following the suck-swallow cycles. Because muscles controlling these behaviors are active in all three types of cycles, we tested the hypothesis that different patterns of electromyographic (EMG) activity in the mylohyoid, hyoglossus, stylohyoid, and thyrohyoid muscles of the pig characterized each cycle type. Anterior mylohyoid EMG activity occurred regularly in every cycle and was used as a cycle marker. Thyrohyoid activity, indicating the pharyngeal swallow, was immediately preceded by increased stylohyoid and hyoglossus activity; it divided the suck-swallow cycle into two phases. Timed from the onset of the suck-swallow cycle, the first phase had a relatively fixed duration while the duration of the second phase, timed from the thyrohyoid, varied directly with cycle duration. In short-duration cycles, the second phase could have a zero duration so that thyrohyoid activity extended into the postswallow cycle. In such cycles, all swallowing activity that occurred after the thyrohyoid EMG and was associated with bolus passage through the pharynx fell into the postswallow cycle. These data suggest that while the activity of some muscles, innervated by trigeminal and cervical plexus nerves, may be time locked to the cycle onset in swallowing, the cycle period itself is not. The postswallow cycle consequently contains variable amounts of pharyngeal swallowing EMG activity. The results exemplify the complexity of the relationship between rhythmic sucking and the swallow.
Modulation of autophagy and ubiquitin-proteasome pathways during ultra-endurance running
Authors: Jamart Cécile , Francaux Marc , Millet Guillaume Y. , Deldicque Louise , Frère Delphine , Féasson Léonard
Published: February 2012

In this study, the coordinated activation of ubiquitin-proteasome pathway (UPP), autophagy-lysosomal pathway (ALP), and mitochondrial remodeling including mitophagy was assessed by measuring protein markers during ultra-endurance running exercise in human skeletal muscle. Eleven male, experienced ultra-endurance athletes ran for 24 h on a treadmill. Muscle biopsy samples were taken from the vastus lateralis muscle 2 h before starting and immediately after finishing exercise. Athletes ran 149.8 ± 16.3 km with an effective running time of 18 h 42 min (±41min). The phosphorylation state of Akt (−74 ± 5%; P < 0.001), FOXO3a (−49 ± 9%; P < 0.001), mTOR Ser2448 (−32 ± 14%; P = 0.028), and 4E-BP1 (−34 ± 7%; P < 0.001) was decreased, whereas AMPK phosphorylation state increased by 247 ± 170% ( P = 0.042). Proteasome β2 subunit activity increased by 95 ± 44% ( P = 0.028), wheras the activities associated with the β1 and β5 subunits remained unchanged. MuRF1 protein level increased by 55 ± 26% ( P = 0.034), whereas MAFbx protein and ubiquitin-conjugated protein levels did not change. LC3bII increased by 554 ± 256% ( P = 0.005), and the form of ATG12 conjugated to ATG5 increased by 36 ± 17% ( P = 0.042). The mitochondrial fission marker phospho-DRP1 increased by 110 ± 47% ( P = 0.003), whereas the fusion marker Mfn1 and the mitophagy markers Parkin and PINK1 remained unchanged. These results fit well with a coordinated regulation of ALP and UPP triggered by FOXO3 and AMPK during ultra-endurance exercise.
p53/HMGB1 Complexes Regulate Autophagy and Apoptosis
Authors: Livesey Kristen M. , Kang Rui , Vernon Philip , Buchser William , Loughran Patricia , Watkins Simon C. , Zhang Lin , Manfredi James J. , Zeh Herbert J. , Li Luyuan , Lotze Michael T. , Tang Daolin
Published: February 2012

The balance between apoptosis (“programmed cell death”) and autophagy (“programmed cell survival”) is important in tumor development and response to therapy. Here, we show that high mobility group box 1 (HMGB1) and p53 form a complex that regulates the balance between tumor cell death and survival. We show that knockout of p53 in HCT116 cells increases expression of cytosolic HMGB1 and induces autophagy. Conversely, knockout of HMGB1 in mouse embryonic fibroblasts increases p53 cytosolic localization and decreases autophagy. p53 is thus a negative regulator of the HMGB1/Beclin 1 complex, and HMGB1 promotes autophagy in the setting of diminished p53. HMGB1-mediated autophagy promotes tumor cell survival in the setting of p53-dependent processes. The HMGB1/p53 complex affects the cytoplasmic localization of the reciprocal binding partner, thereby regulating subsequent levels of autophagy and apoptosis. These insights provide a novel link between HMGB1 and p53 in the cross-regulation of apoptosis and autophagy in the setting of cell stress, providing insights into their reciprocal roles in carcinogenesis. Cancer Res; 72(8); 1996–2005. ©2012 AACR.
CDK8 Maintains Tumor Dedifferentiation and Embryonic Stem Cell Pluripotency
Authors: Adler Adam S. , McCleland Mark L. , Truong Tom , Lau Shari , Modrusan Zora , Soukup Tim M. , Roose-Girma Merone , Blackwood Elizabeth M. , Firestein Ron
Published: February 2012

CDK8 is a cyclin-dependent kinase that mediates transcriptional control of pathways linked to both cancer and stem cells. In this study, we show that CDK8 is required for both tumor growth and maintenance of tumor dedifferentiation in vivo and uncover a common role for CDK8 in controlling cancer and stem cell function. Acute CDK8 loss in vivo strongly inhibited tumor growth and promoted differentiation. Transcriptional profiling identified a set of embryonic stem cell–related genes that are activated by CDK8 in cancer. Consistent with this, we found that CDK8 expression correlated to the embryonic stem cell pluripotency state and loss of CDK8 caused embryonic stem cells to differentiate. This effect was, at least partially, mediated by the ability of CDK8 to regulate MYC protein and downstream MYC target gene expression. Similar regulation of MYC target genes by CDK8 was observed in colon tumor cells, and increased expression of a CDK8-regulated, embryonic stem cell MYC target gene signature was associated with loss of differentiation and poor outcome in primary human colon cancers. Together, these observations reveal that CDK8 acts, at least in part, through MYC to maintain both tumors and embryonic stem cells in an undifferentiated state. This raises the intriguing possibility that targeting CDK8 therapeutically may specifically inhibit the stem-like properties of cancer cells. Cancer Res; 72(8); 2129–39. ©2012 AACR.
Molecular Pathways: Regulation and Therapeutic Implications of Multidrug Resistance
Authors: Chen Kevin G. , Sikic Branimir I.
Published: February 2012

Multidrug transporters constitute major mechanisms of MDR in human cancers. The ABCB1 (MDR1) gene encodes a well-characterized transmembrane transporter, termed P-glycoprotein (P-gp), which is expressed in many normal human tissues and cancers. P-gp plays a major role in the distribution and excretion of drugs and is involved in intrinsic and acquired drug resistance of cancers. The regulation of ABCB1 expression is complex and has not been well studied in a clinical setting. In this review, we elucidate molecular signaling and epigenetic interactions that govern ABCB1 expression and the development of MDR in cancer. We focus on acquired expression of ABCB1 that is associated with genomic instability of cancer cells, including mutational events that alter chromatin structures, gene rearrangements, and mutations in tumor suppressor proteins (e.g., mutant p53), which guard the integrity of genome. In addition, epigenetic modifications of the ABCB1 proximal and far upstream promoters by either demethylation of DNA or acetylation of histone H3 play a pivotal role in inducing ABCB1 expression. We describe a molecular network that coordinates genetic and epigenetic events leading to the activation of ABCB1. These mechanistic insights provide additional translational targets and potential strategies to deal with clinical MDR. Clin Cancer Res; 18(7); 1863–9. ©2012 AACR.
miRNA Profiling in Colorectal Cancer Highlights miR-1 Involvement in MET-Dependent Proliferation
Authors: Reid James F. , Sokolova Viktorija , Zoni Eugenio , Lampis Andrea , Pizzamiglio Sara , Bertan Claudia , Zanutto Susanna , Perrone Federica , Camerini Tiziana , Gallino Gianfrancesco , Verderio Paolo , Leo Ermanno , Pilotti Silvana , Gariboldi Manuela , Pierotti Marco A.
Published: February 2012

Altered expression of miRNAs is associated with development and progression of various human cancers by regulating the translation of oncogenes and tumor suppressor genes. In colorectal cancer, these regulators complement the Vogelstein multistep model of pathogenesis and have the potential of becoming a novel class of tumor biomarkers and therapeutic targets. Using quantitative real-time PCR, we measured the expression of 621 mature miRNAs in 40 colorectal cancers and their paired normal tissues and identified 23 significantly deregulated miRNAs. We subsequently evaluated their association with clinical characteristics of the samples and presence of alterations in the molecular markers of colorectal cancer progression. Expression levels of miR-31 were correlated with CA19-9 and miR-18a, miR-21, and miR-31 were associated with mutations in APC gene. To investigate the downstream regulation of the differentially expressed miRNAs identified, we integrated putative mRNA target predictions with the results of a meta-analysis of seven public gene expression datasets of normal and tumor samples of colorectal cancer patients. Many of the colorectal cancer deregulated miRNAs computationally mapped to targets involved in pathways related to progression. Here one promising candidate pair (miR-1 and MET) was studied and functionally validated. We show that miR-1 can have a tumor suppressor function in colorectal cancer by directly downregulating MET oncogene both at RNA and protein level and that reexpression of miR-1 leads to MET-driven reduction of cell proliferation and motility, identifying the miR-1 downmodulation as one of the events that could enhance colorectal cancer progression. Mol Cancer Res; 10(4); 504–15. ©2012 AACR.
Reclassifying Formerly Indeterminate Thyroid FNAs Using the Bethesda System Reduces the Number of Inconclusive Cases
Authors: Song Ju Young , Chu Young Chae , Kim Lucia , Park In Suh , Han Jee Young , Kim Joon Mee
Published: February 2012

Objective: To evaluate the effectiveness of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) and to analyze the causes of unclear diagnoses following BSRTC adoption. Study Design: According to the BSRTC, we reclassified cytologic samples originally diagnosed as ‘indeterminate’ with sequential surgical resection. Then, we analyzed the causes of cases, which were recategorized as ‘atypia undetermined significance/follicular lesion of undetermined significance (AUS/FLUS)’. Results: According to the BSRTC, 154 ‘indeterminate’ cases were reclassified as follows: unsatisfactory, n = 5 (3.2%); benign, n = 43 (27.9%); AUS/FLUS, n = 77 (50.0%); suspicious for a follicular neoplasm, n = 7 (7.1%); suspicious for a Hürthle cell neoplasm, n = 4 (2.6%); suspicious for malignancy, n = 15 (9.7%), and malignancy, n = 3 (1.9%). Then, the AUS/FLUS group was analyzed according to the scenarios proposed by the BSRTC. Fifty-nine (58.9%) cases of AUS/FLUS were due to suboptimal preparation. In addition, papillary microcarcinoma and coexisting Hashimoto’s thyroiditis caused inconclusive diagnoses. Conclusion: The BSRTC can be easily applied to thyroid fine-needle aspiration. We were able to reclassify indeterminate thyroid nodules into more detailed categories and thus reduce the number of cases classified as indeterminate. However, suboptimal preparation, papillary microcarcinoma, and coexisting Hashimoto’s thyroiditis precluded cytopathologists from making definitive diagnoses.
The Role of Axillary Lymph Node Fine Needle Aspiration in Breast Cancer Staging prior to Chemotherapy with Histological Correlation
Authors: Monaco Sara E. , Colaizzi Amy , Kanbour Anisa , Ibrahim Ahmed S. , Kanbour-Shakir Amal
Published: February 2012

Objective: Axillary lymph node (LN) sampling is important for breast cancer staging and can be performed using fine needle aspiration (FNA). The aim of this study is to review the axillary LN FNAs performed at our institution prior to treatment, and to correlate their results with the available LN histology in order to evaluate the diagnostic utility of FNA. Study Design: A total of 130 cases were retrospectively identified over a 1-year period and reviewed. The FNA findings were correlated with the histological findings in 65 (50%) LN core biopsies, 43 (33%) sentinel LN biopsies, and 22 (17%) axillary dissections. Results: One hundred and thirteen FNA cases (89%) correlated with the histology, while 14 cases (11%) did not correlate, including 1 false positive and 13 false negatives. Of the false-negative cases, metastases in the biopsy ranged from isolated tumor cells to 5 mm in the greatest dimension. The overall sensitivity was 85%, specificity 98%, positive predictive value 99%, and negative predictive value 75%. Conclusion: Pretherapy staging of breast cancer by FNA is a useful diagnostic modality with a high specificity and positive predictive value. Due to false-negative diagnoses, a negative FNA should be followed up with further LN sampling.
Immunomarkers in Gynecologic Cytology: The Search for the Ideal ‘Biomolecular Papanicolaou Test’
Authors: Pinto Álvaro P. , Degen Martin , Villa Luisa Lina , Cibas Edmund S.
Published: February 2012

Harnessing the knowledge we have gained on the cell cycle disruption caused by human papillomaviruses (HPV) will likely lead to improved screening modalities for cervical cancer and its precursors. An easily applied biomarker that has high specificity and sensitivity would represent an attractive alternative or complement to cytology and HPV testing. To date, a number of promising markers have been investigated. These include p16INK4A, MIB-1, BD-ProEx C, and L1. Newer possibilities involve a variety of gene products associated with aberrations of chromosome 3q, such as telomerase, p63, and PIK3CA, as well the combination of biomarkers such as p16INK4A and MIB-1 in the same assay. Although none of them has yet been incorporated into screening algorithms or found its way into routine practice, their performance characteristics remain a focus of current investigations. This review summarizes what we know and where we hope to go in translating basic pathobiology into clinical practice.