bluuebunny/crossref_metadata_2025 huggingface dataset:
STAT-5 Regulates Transcription of the Topoisomerase IIβ-Binding Protein 1 (TopBP1) Gene To Activate the ATR Pathway and Promote Human Papillomavirus Replication
Authors: Hong Shiyuan , Cheng Shouqiang , Iovane Andre , Laimins Laimonis A.
Published: December 2015

The life cycle of high-risk human papillomaviruses (HPVs) is dependent upon epithelial differentiation. Following infection of basal cells, HPV genomes are stably maintained at low copy numbers, and productive replication or amplification is restricted to highly differentiated suprabasal cells. In high-risk HPV infections, the ATM pathway is constitutively activated in the absence of external DNA-damaging agents and is required for productive viral replication. The ataxia telangiectasia (ATM) pathway repairs double-strand breaks in DNA, while the ataxia telangiectasia and Rad3-related (ATR) pathway targets single-strand breaks. Our studies show that the ATR pathway, like the ATM pathway, is activated in HPV-positive cells and that inhibitors of ATR or CHK1 phosphorylation block both amplification and late viral gene expression in differentiated cells while moderately reducing stable copy numbers in undifferentiated cells. TopBP1 is a critical upstream activator of the ATR pathway and is expressed at elevated levels in HPV-positive cells. This increased expression of TopBP1 is necessary for ATR/CHK1 activation in HPV-positive cells, and knockdown blocks amplification. Furthermore, TopBP1 activation is shown to be regulated at the level of transcription initiation by the innate immune regulator STAT-5, which is activated by HPV proteins. STAT-5 has also been shown to be a regulator of the ATM response, demonstrating that these two pathways are coordinately regulated in HPV-positive cells. These findings identify a novel link between the innate immune response and activation of the ATR DNA damage response in regulating the life cycle of high-risk HPVs.

IMPORTANCE
High-risk human papillomaviruses (HPVs) are the causative agents of cervical and other anogenital cancers, as well as many oral cancers. HPVs infect epithelial cells and restrict productive viral replication or amplification and virion production to differentiated cells. Our studies demonstrate that HPVs activate the ATR single-strand DNA repair pathway and this activation is necessary for HPV genome amplification. The innate immune regulator STAT-5 is shown to regulate transcription of the ATR binding factor TopBP1, and this is critical for the induction of the ATR pathway. Our study identifies important links between innate immune signaling, the ATR DNA damage pathway, and productive HPV replication that may lead to the characterization of new targets for the development of therapeutics to treat HPV-induced infections.
Policy change eliminating body checking in non-elite ice hockey leads to a threefold reduction in injury and concussion risk in 11- and 12-year-old players
Authors: Black Amanda M , Macpherson Alison K , Hagel Brent E , Romiti Maria A , Palacios-Derflingher Luz , Kang Jian , Meeuwisse Willem H , Emery Carolyn A
Published: December 2015

Background

In ice hockey, body checking is associated with an increased risk of injury. In 2011, provincial policy change disallowed body checking in non-elite Pee Wee (ages 11–12 years) leagues.

Objective

To compare the risk of injury and concussion between non-elite Pee Wee ice hockey players in leagues where body checking is permitted (2011–12 Alberta, Canada) and leagues where policy change disallowed body checking (2011–12 Ontario, Canada).

Method

Non-elite Pee Wee players (lower 70%) from Alberta (n=590) and Ontario (n=281) and elite Pee Wee players (upper 30%) from Alberta (n=294) and Ontario (n=166) were recruited to participate in a cohort study. Baseline information, injury and exposure data was collected using validated injury surveillance.

Results

Based on multiple Poisson regression analyses (adjusted for clustering by team, exposure hours, year of play, history of injury/concussion, level of play, position and body checking attitude), the incidence rate ratio (IRR) associated with policy allowing body checking was 2.97 (95% CI 1.33 to 6.61) for all game injury and 2.83 (95% CI 1.09 to 7.31) for concussion. There were no differences between provinces in concussion [IRR=1.50 (95% CI 0.84 to 2.68)] or injury risk [IRR=1.22 (95% CI 0.69 to 2.16)] in elite levels of play where both provinces allowed body checking.

Conclusions

The rate of injury and concussion were threefold greater in non-elite Pee Wee ice hockey players in leagues where body checking was permitted. The rate of injury and concussion did not differ between provinces in elite levels, where body checking was allowed.
Sidecut radius and kinetic energy: equipment designed to reduce risk of severe traumatic knee injuries in alpine giant slalom ski racing
Authors: Kröll Josef , Spörri Jörg , Gilgien Matthias , Schwameder Hermann , Müller Erich
Published: December 2015

Background

Kinetic energy (Ekin) increases with speed by the power of 2 and is considered a major risk factor for injuries in alpine ski racing. There is no empirical knowledge about the effect of ski geometry on Ekin. Consequently, the aim of this study was to investigate the influence of sidecut radius on the progress of Ekinwhile skiing through a multigate section in giant slalom (GS).

Methods

5 European-Cup level athletes skied on three different pairs of GS skis varying in sidecut radii (30, 35 and 40 m). Each athlete's position over time within a six gate section (including flat and steep terrain) was captured by the use of a differential Global Navigational Satellite System. Ekin, speed, time and path length were analysed for each pair of skis used.

Results

When using skis with greater sidecut radius, average Ekinwas significantly lower over the entire six gate section, but not locally at every turn cycle. Particular decreases of Ekinwere observed for both turns on the flat terrain, as well as for the turn at the terrain transition and the first turn on the steep terrain. The observed decreases in Ekinwere found to be primarily explainable by increases in turn time.

Conclusions

With respect to typical sport mechanisms that cause severe knee injuries, using skis with greater sidecut radius potentially provides additional injury preventative gain, particularly in specific areas within a run. However, this injury preventative gain during falls in GS should not be overestimated.
Study of static lateral behavior of battered pile group foundation at I-10 Twin Span Bridge using three-dimensional finite element modeling
Authors: Souri Ahmad , Abu-Farsakh Murad , Voyiadjis George
Published: December 2015

In this study, the static lateral behavior of a battered pile group foundation was investigated using three-dimensional finite element (FE) analysis. The FE model was used to simulate the static lateral load test that was performed during the construction of the I-10 Twin Span Bridge over Lake Pontchartrain, La., in which two adjacent bridge piers were pulled against each other. The pier of interest was supported by 24, 1:6 batter, 34 m long piles in a 6 × 4 row configuration. The FE model of the battered pile group was developed in Abaqus and verified using the results from the field test. The model utilized an advanced constitutive model for concrete, which allowed distinct behavior in tension and compression, and introduced damage to the concrete stiffness. The soil domain comprised of several layers in which the constitutive behavior of clay layers was modeled using the anisotropic modified Cam-clay (AMCC) model, and for sands using the elastic perfectly plastic Drucker–Prager (DP) model. FE results showed good agreement with the results of the lateral load test in terms of lateral deformations and bending moments. The results showed that the middle rows carried a larger share of lateral load than the first and the last rows. The pile group resisted a maximum lateral load of 2494 t at which the piles were damaged within a 6 m zone from the bottom of the pile cap. The edge piles carried larger internal forces and exhibited more damage compared to the inner piles. The soil resistance profiles showed that soil layering influenced the distribution of resistance between the soil layers. A series of p–y curves were extracted from the FE model, and then used to study the influence of the group effect on the soil resistance. The p–y curves showed that the group effect reduced the soil resistance in all rows, with the lowest resistance in the third row. Finally, the p-multipliers were calculated using the extracted p–y curves, and compared to the reported p-multipliers for vertical pile groups.
Bayesian model averaging for the prediction of water main failure for small to large Canadian municipalities
Authors: Kabir Golam , Tesfamariam Solomon , Sadiq Rehan
Published: December 2015

Water utilities often rely on water main failure prediction models for developing preventive or proactive repair and replacement action programs. Due to inherent uncertainties in modeling, it is challenging to understand the water main failure processes and to predict the failure effectively. In this study, Bayesian model averaging (BMA) method is presented to identify the influential covariates and to predict the failure rates of water mains considering model uncertainties. To accredit the proposed model, it is implemented to predict the failure of pipes of the water distribution network of the City of Kelowna, BC and Greater Vernon Water, BC, Canada. Results indicate that the proposed BMA approach captures the effect of the potential explanatory variables more effectively through the posterior probabilities in contrast to that of the p-value given by the classical regression analysis. Moreover, BMA approach performs better compared to classical regression analysis when limited pipe failure data are available.
Numerical simulation on the reduction of flow heterogeneity in the biofilter media
Authors: Yan Weiwei , Liu Xingli , Wu Jie , Wei Yikun , Xu Peng
Published: December 2015

The biofilters are the ideal solutions for the biological treatment of air pollutants. However, there exists strong flow heterogeneity in porous media that degrades the removal efficiency of biofilters. Thus, the effects of Darcy number, Reynolds number and porosity of porous media on the reduction of flow heterogeneity in three biofilter models were numerically studied by the lattice Boltzmann method. The simulation results lead to three conclusions: (1) The Darcy number has dominant influence on the flow heterogeneity in the biofilters. The reduction of flow heterogeneity can be realized by designing a comparatively low Darcy number. (2) The Reynolds number has obvious effect on the flow heterogeneity in the biofilters. However, the reduction of flow heterogeneity cannot be effectively established by regulating the Reynolds number. (3) The property of porous media greatly influences the flow heterogeneity in the biofilters. The present results are helpful for the optimized design of practical biofilter models.
Asymptotic expansion of pair production probability in a time-dependent electric field
Authors: Arai Takashi
Published: December 2015

We study particle creation in a single pulse of an electric field in scalar quantum electrodynamics. We investigate the parameter condition for the case where the dynamical pair creation and Schwinger mechanism respectively dominate. Then, an asymptotic expansion for the particle distribution in terms of the time interval of the applied electric field is derived. We compare our result with particle creation in a constant electric field with a finite-time interval. These results coincide in an extremely strong field, however they differ in general field strength. We interpret the reason of this difference as a nonperturbative effect of high-frequency photons in external electric fields. Moreover, we find that the next-to-leading-order term in our asymptotic expansion coincides with the derivative expansion of the effective action.
Decays Z → γγ and Z → gg in the Standard Model Extension
Authors: Castro-Medina J. , Novales-Sanchez H. , Toscano J. J. , Tututi E. S.
Published: December 2015

The [Formula: see text] and [Formula: see text] decays are studied in the context of the renormalizable version of the Standard Model Extension. The [Formula: see text]-odd [Formula: see text] bilinear interaction, which involves the constant background field [Formula: see text] and which has been a subject of interest in literature, is considered. It is shown that the [Formula: see text] and [Formula: see text] decays, which are strictly zero in the standard model, can be generated radiatively at the one-loop level. It is found that these decays are gauge invariant and free of ultraviolet divergences, and that the corresponding decay widths only depend on the spatial component of the background field [Formula: see text].
Chaos in the Belousov–Zhabotinsky reaction
Authors: Field Richard J.
Published: December 2015

The dynamics of reacting chemical systems is governed by typically polynomial differential equations that may contain nonlinear terms and/or embedded feedback loops. Thus the dynamics of such systems may exhibit features associated with nonlinear dynamical systems, including (among others): temporal oscillations, excitability, multistability, reaction-diffusion-driven formation of spatial patterns, and deterministic chaos. These behaviors are exhibited in the concentrations of intermediate chemical species. Bifurcations occur between particular dynamic behaviors as system parameters are varied. The governing differential equations of reacting chemical systems have as variables the concentrations of all chemical species involved, as well as controllable parameters, including temperature, the initial concentrations of all chemical species, and fixed reaction-rate constants. A discussion is presented of the kinetics of chemical reactions as well as some thermodynamic considerations important to the appearance of temporal oscillations and other nonlinear dynamic behaviors, e.g., deterministic chaos. The behavior, chemical details, and mechanism of the oscillatory Belousov–Zhabotinsky Reaction (BZR) are described. Furthermore, experimental and mathematical evidence is presented that the BZR does indeed exhibit deterministic chaos when run in a flow reactor. The origin of this chaos seems to be in toroidal dynamics in which flow-driven oscillations in the control species bromomalonic acid couple with the BZR limit cycle.
The relative Hilbert scheme of projection morphisms
Authors: Kim Hosung
Published: December 2015

Let [Formula: see text] be a smooth hypersurface of degree [Formula: see text] in a projective space [Formula: see text] and take a point [Formula: see text] in [Formula: see text]. Let [Formula: see text] be the relative Hilbert scheme parametrizing zero-dimensional subscheme, of length [Formula: see text], of fibers of the projection morphism [Formula: see text] from [Formula: see text]. In this paper we present an embedding of the relative Hilbert scheme [Formula: see text] into a weighted projective space and describe its defining ideal for general [Formula: see text]. We also study line bundles on the relative Hilbert scheme [Formula: see text] for [Formula: see text] and general [Formula: see text].
Transductive Conformal Prediction
Authors: Vovk Vladimir
Published: December 2015

This paper discusses transductive versions of conformal predictors and inductive conformal predictors. The transductive versions are computationally inefficient for long test sequences, but it turns out that apparently crude “Bonferroni predictors” are about as good in their informational efficiency and vastly superior in computational efficiency. The paper explores transductive predictors both theoretically and experimentally, in the latter case using the standard USPS data set of handwritten digits.
Conformal Region Classification with Instance-Transfer Boosting
Authors: Zhou Shuang , Smirnov Evgueni Nikolaevich , Peeters Ralf
Published: December 2015

Conformal region classification focuses on developing region classifiers; i.e., classifiers that output regions (sets) of classes for new test instances.2,13,16 Conformal region classifiers have been proven to be valid for any significance level [Formula: see text] in the sense that the probability the class regions do not contain the true instances' classes does not exceed [Formula: see text]. In practice, however, conformal region classifiers need to be also efficient; i.e., they have to output non-empty and relatively small class regions.

In this paper we show that conformal region classification can benefit from instance transfer learning. Our new approach consists of the basic conformal region classifier with a nonconformity function that implements instance transfer. We propose to learn such a function using a new multi-class Transfer AdaBoost.M1 algorithm. The function and its relation to the conformal region classification are theoretically justified. The experiments showed that our approach is valid for any significance level [Formula: see text] and its efficiency can be improved with instance transfer.
Hypergraphical Conformal Predictors
Authors: Fedorova Valentina , Gammerman Alex , Nouretdinov Ilia , Vovk Vladimir
Published: December 2015

Conformal predictors are usually defined and studied under the exchangeability assumption. However, their definition can be extended to a wide class of statistical models, called online compression models, while retaining their property of automatic validity. This paper is devoted to conformal prediction under hypergraphical models that are more specific than the exchangeability model. Namely, we define two natural classes of conformity measures for such hypergraphical models and study the corresponding conformal predictors empirically on benchmark LED data sets. Our experiments show that they are more efficient than conformal predictors that use only the exchangeability assumption.
A note on the existence of nontrivial homomorphism En(R) → En−1(R)
Authors: You Hong
Published: December 2015

We show that there is no nontrivial group homomorphism [Formula: see text] over commutative local rings and division rings for [Formula: see text], respectively. It gives a negative answer to Ye’s problem (see [S. K. Ye, Low-dimensional representations of matrix group actions on CAT(0) spaces and manifolds, J. Algebra 409 (2014) 219–243]) for the above rings.
Erasures and perturbations of g-frames and fusion frames in Hilbert C∗-modules
Authors: Azandaryani Morteza Mirzaee
Published: December 2015

In this paper, we study the erasures of submodules of a fusion frame in Hilbert [Formula: see text]-modules and we present some sufficient conditions under which a sequence remains a standard fusion frame after deletion of some submodules. We also introduce a new perturbation for g-frames and fusion frames in Hilbert [Formula: see text]-modules and it is shown that under some conditions g-frames and fusion frames are stable under this perturbation. We generalize some of the results obtained for perturbations of g-frames and fusion frames, especially we consider perturbations of direct sums, duals and approximate duals of g-frames.
Plancherel measures for coverings of p-adic SL2(F)
Authors: Goldberg David , Szpruch Dani
Published: December 2015

In these notes, we compute the Plancherel measures associated with genuine principal series representations of [Formula: see text]-fold covers of [Formula: see text]-adic [Formula: see text]. Along the way, we also compute a higher dimensional metaplectic analog of Shahidi local coefficients. Our method involves new functional equations utilizing the Tate [Formula: see text]-factor and a metaplectic counterpart. As an application, we prove an irreducibility theorem.
More parity results for broken 9-diamond partitions
Authors: Dai Haobo , Wang Yudong
Published: December 2015

Broken [Formula: see text]-diamond partitions were introduced in 2007 by Andrews and Paule. Let [Formula: see text] denote the number of broken [Formula: see text]-diamond partitions of [Formula: see text]. In 2010, Radu and Sellers provided many beautiful congruences for [Formula: see text] modulo 2 when [Formula: see text]. Among them when [Formula: see text], they showed that [Formula: see text] when [Formula: see text]. In this article, by using properties of modular forms, we have completely determined the behavior of [Formula: see text] and [Formula: see text] modulo 2. As a consequence, we obtain many more congruences for [Formula: see text] modulo 2.
Two-stage test with possibility of rejection of decision
Authors: Hormozinejad Farshin
Published: December 2015

The multiple statistical hypotheses two-stage testing with possibility of rejecting of decision to make choice between hypotheses concerning the pair of groups of probability distributions is considered such that in the first stage one group of distributions is distinguished and then in the second stage, the true distribution is denoted between mentioned group of probability distributions. Description of characteristics of logarithmically asymptotically optimal (LAO) hypotheses testing with possibility of decision rejection and the matrix of optimal asymptotically interdependencies of all pairs of the error probability exponents or reliabilities are studied. The goal of research is to express the optimal functional relation between the reliabilities of LAO hypotheses testing by a pair of stages and to compare with the case of similar one-stage testing.
The bi-normal fields on spacelike surfaces in ℝ14
Authors: Cuong Dang Van
Published: December 2015

A normal field [Formula: see text] on a spacelike surface in [Formula: see text] is called bi-normal if [Formula: see text], the determinant of the Weingarten map associated to [Formula: see text], is zero. In this paper, we give a criterion to check if a normal field is bi-normal. Then we study the relationship between the spacelike pseudo-planar surfaces and spacelike pseudo-umbilical surfaces. We also study the bi-normal fields on spacelike ruled surfaces and spacelike surfaces of revolution.
On mutually permutable products of generalized supersoluble subgroups of finite groups
Authors: Myslovets E. N.
Published: December 2015

Let [Formula: see text] be a class of finite simple groups. We say that a finite group [Formula: see text] is a [Formula: see text]-group if all composition factors of [Formula: see text] are contained in [Formula: see text]. A group [Formula: see text] is called [Formula: see text]-supersoluble if every chief [Formula: see text]-factor of [Formula: see text] is a simple group. In this paper, properties of mutually permutable products of [Formula: see text]-supersoluble finite groups are studied. Some earlier results on mutually permutable products of [Formula: see text]-supersoluble groups (SC-groups) appear as particular cases.
Performance Comparison of a Truck Refrigeration System with R404A, R134a, R1234yf, and R744 Refrigerants under Frosting Conditions
Authors: Shin Yunchan , Cho Honghyun
Published: December 2015

A new refrigerant is needed because the GWP of the R404A and R134a that are used in existing refrigerated trucks and automotive air conditioners is so high. This study predicts cooling performance by using an analytical model, for refrigeration systems using R404A and R134a. Furthermore, the performances of those systems were compared with those of alternative refrigeration systems using R1234yf and R744. The performance data of the analytical model had a trend similar to that of the experimental data: the average error between the analytical and experimental results was within 5.4%. The frost thickness of the R404A system for all operating conditions was about 2.4–3.7% larger than that of other systems because the evaporating temperature of the R404A system was lower than that for other refrigerants. For various operating conditions, the coefficient of performance (COP) of the R134a system was higher than that of other systems, while the R744 system showed the lowest performance. However, the COP reduction of the R744 system with operating time was the smallest because the thermodynamic properties of R744 were very superior. In addition, the frost thickness was seriously affected by the variations of indoor air temperature and compressor rotation speeds, and the system performance decreased significantly for severe operating conditions.
A Process for Systematic Development of Symbolic Models for Activity Recognition
Authors: Yordanova Kristina , Kirste Thomas
Published: December 2015

Several emerging approaches to activity recognition (AR) combine symbolic representation of user actions with probabilistic elements for reasoning under uncertainty. These approaches provide promising results in terms of recognition performance, coping with the uncertainty of observations, and model size explosion when complex problems are modelled. But experience has shown that it is not always intuitive to model even seemingly simple problems. To date, there are no guidelines for developing such models. To address this problem, in this work we present a development process for building symbolic models that is based on experience acquired so far as well as on existing engineering and data analysis workflows. The proposed process is a first attempt at providing structured guidelines and practices for designing, modelling, and evaluating human behaviour in the form of symbolic models for AR. As an illustration of the process, a simple example from the office domain was developed. The process was evaluated in a comparative study of an intuitive process and the proposed process. The results showed a significant improvement over the intuitive process. Furthermore, the study participants reported greater ease of use and perceived effectiveness when following the proposed process. To evaluate the applicability of the process to more complex AR problems, it was applied to a problem from the kitchen domain. The results showed that following the proposed process yielded an average accuracy of 78%. The developed model outperformed state-of-the-art methods applied to the same dataset in previous work, and it performed comparably to a symbolic model developed by a model expert without following the proposed development process.
Weaker Forms of Monotonicity for Declarative Networking
Authors: Ameloot Tom J. , Ketsman Bas , Neven Frank , Zinn Daniel
Published: December 2015

The CALM-conjecture, first stated by Hellerstein [2010] and proved in its revised form by Ameloot et al. [2013] within the framework of relational transducer networks, asserts that a query has a coordination-free execution strategy if and only if the query is monotone. Zinn et al. [2012] extended the framework of relational transducer networks to allow for specific data distribution strategies and showed that the nonmonotone win-move query is coordination-free for domain-guided data distributions. In this article, we extend the story by equating increasingly larger classes of coordination-free computations with increasingly weaker forms of monotonicity and present explicit Datalog variants that capture each of these classes. One such fragment is based on stratified Datalog where rules are required to be connected with the exception of the last stratum. In addition, we characterize coordination-freeness as those computations that do not require knowledge about all other nodes in the network, and therefore, can not globally coordinate. The results in this article can be interpreted as a more fine-grained answer to the CALM-conjecture.
Compiler-Driven Software Speculation for Thread-Level Parallelism
Authors: Yiapanis Paraskevas , Brown Gavin , Luján Mikel
Published: December 2015

Current parallelizing compilers can tackle applications exercising regular access patterns on arrays or affine indices, where data dependencies can be expressed in a linear form. Unfortunately, there are cases that independence between statements of code cannot be guaranteed and thus the compiler conservatively produces sequential code. Programs that involve extensive pointer use, irregular access patterns, and loops with unknown number of iterations are examples of such cases. This limits the extraction of parallelism in cases where dependencies are rarely or never triggered at runtime. Speculative parallelism refers to methods employed during program execution that aim to produce a valid parallel execution schedule for programs immune to static parallelization. The motivation for this article is to review recent developments in the area of compiler-driven software speculation for thread-level parallelism and how they came about. The article is divided into two parts. In the first part the fundamentals of speculative parallelization for thread-level parallelism are explained along with a design choice categorization for implementing such systems. Design choices include the ways speculative data is handled, how data dependence violations are detected and resolved, how the correct data are made visible to other threads, or how speculative threads are scheduled. The second part is structured around those design choices providing the advances and trends in the literature with reference to key developments in the area. Although the focus of the article is in software speculative parallelization, a section is dedicated for providing the interested reader with pointers and references for exploring similar topics such as hardware thread-level speculation, transactional memory, and automatic parallelization.
May-Happen-in-Parallel Analysis for Actor-Based Concurrency
Authors: Albert Elvira , Flores-Montoya Antonio , Genaim Samir , Martin-Martin Enrique
Published: December 2015

This article presents a
may-happen-in-parallel
(MHP) analysis for languages with
actor-based concurrency
. In this concurrency model, actors are the concurrency
units
such that, when a method is invoked on an actor
a
2
from a task executing on actor
a
1
, statements of the current task in
a
1
may run in parallel with those of the (asynchronous) call on
a
2
, and with those of transitively invoked methods. The goal of the MHP analysis is to identify pairs of statements in the program that may run in parallel in any execution. Our MHP analysis is formalized as a method-level (
local
) analysis whose information can be modularly composed to obtain application-level (
global
) information. The information yielded by the MHP analysis is essential to infer more complex properties of actor-based concurrent programs, for example, data race detection, deadlock freeness, termination, and resource consumption analyses can greatly benefit from the MHP relations to increase their accuracy. We report on MayPar, a prototypical implementation of an MHP static analyzer for a distributed asynchronous language.
The human milk oligosaccharide 2′-fucosyllactose augments the adaptive response to extensive intestinal
Authors: Mezoff Ethan A. , Hawkins Jennifer A. , Ollberding Nicholas J. , Karns Rebekah , Morrow Ardythe L. , Helmrath Michael A.
Published: December 2015

Intestinal resection resulting in short bowel syndrome (SBS) carries a heavy burden of long-term morbidity, mortality, and cost of care, which can be attenuated with strategies that improve intestinal adaptation. SBS infants fed human milk, compared with formula, have more rapid intestinal adaptation. We tested the hypothesis that the major noncaloric human milk oligosaccharide 2′-fucosyllactose (2′-FL) contributes to the adaptive response after intestinal resection. Using a previously described murine model of intestinal adaptation, we demonstrated increased weight gain from 21 to 56 days ( P < 0.001) and crypt depth at 56 days ( P < 0.0095) with 2′-FL supplementation after ileocecal resection. Furthermore, 2′-FL increased small bowel luminal content microbial alpha diversity following resection ( P < 0.005) and stimulated a bloom in organisms of the genus Parabacteroides (log2-fold = 4.1, P = 0.035). Finally, transcriptional analysis of the intestine revealed enriched ontologies and pathways related to antimicrobial peptides, metabolism, and energy processing. We conclude that 2′-FL supplementation following ileocecal resection increases weight gain, energy availability through microbial community modulation, and histological changes consistent with improved adaptation.
The role of microRNAs in cardiac development and regenerative capacity
Authors: Katz Michael G. , Fargnoli Anthony S. , Kendle Andrew P. , Hajjar Roger J. , Bridges Charles R.
Published: December 2015

The mammalian heart has long been considered to be a postmitotic organ. It was thought that, in the postnatal period, the heart underwent a transition from hyperplasic growth (more cells) to hypertrophic growth (larger cells) due to the conversion of cardiomyocytes from a proliferative state to one of terminal differentiation. This hypothesis was gradually disproven, as data were published showing that the myocardium is a more dynamic tissue in which cardiomyocyte karyokinesis and cytokinesis produce new cells, leading to the hyperplasic regeneration of some of the muscle mass lost in various pathological processes. microRNAs have been shown to be critical regulators of cardiomyocyte differentiation and proliferation and may offer the novel opportunity of regenerative hyperplasic therapy. Here we summarize the relevant processes and recent progress regarding the functions of specific microRNAs in cardiac development and regeneration.
KLF5 mediates vascular remodeling via HIF-1α in hypoxic pulmonary hypertension
Authors: Li Xiaochen , He Yuanzhou , Xu Yongjian , Huang Xiaomin , Liu Jin , Xie Min , Liu Xiansheng
Published: December 2015

Hypoxic pulmonary hypertension (HPH) is characterized by active vasoconstriction and profound vascular remodeling. KLF5, a zinc-finger transcription factor, is involved in the excessive proliferation and apoptotic resistance phenotype associated with monocrotaline-induced pulmonary hypertension. However, the molecular mechanisms of KLF5-mediated pathogenesis of HPH are largely undefined. Adult male Sprague-Dawley rats were exposed to normoxia or hypoxia (10% O2) for 4 wk. Hypoxic rats developed pulmonary arterial remodeling and right ventricular hypertrophy with significantly increased right ventricular systolic pressure. The levels of KLF5 and hypoxia-inducible factor-1α (HIF-1α) were upregulated in distal pulmonary arterial smooth muscle from hypoxic rats. The knockdown of KLF5 via short-hairpin RNA attenuated chronic hypoxia-induced hemodynamic and histological changes in rats. The silencing of either KLF5 or HIF-1α prevented hypoxia-induced (5%) proliferation and migration and promoted apoptosis in human pulmonary artery smooth muscle cells. KLF5 was immunoprecipitated with HIF-1α under hypoxia and acted as an upstream regulator of HIF-1α. The cell cycle regulators cyclin B1 and cyclin D1 and apoptosis-related proteins including bax, bcl-2, survivin, caspase-3, and caspase-9, were involved in the regulation of KLF5/HIF-1α-mediated cell survival. This study demonstrated that KLF5 plays a crucial role in hypoxia-induced vascular remodeling in an HIF-1α-dependent manner and provided a better understanding of the pathogenesis of HPH.
Evidence for a mitochondrial angiotensin-(1–7) system in the kidney
Authors: Wilson Bryan A. , Nautiyal Manisha , Gwathmey TanYa M. , Rose James C. , Chappell Mark C.
Published: December 2015

Evidence for an intracellular renin-angiotensin system (RAS) in various cell organelles now includes the endoplasmic reticulum, nucleus, and mitochondria (Mito). Indeed, angiotensin (ANG) AT1 and AT2 receptor subtypes were functionally linked to Mito respiration and nitric oxide production, respectively, in previous studies. We undertook a biochemical analysis of the Mito RAS from male and female sheep kidney cortex. Mito were isolated by differential centrifugation followed by a discontinuous Percoll gradient and were coenriched in Mito membrane markers VDAC and ATP synthase, but not β-actin or cathepsin B. Two distinct renin antibodies identified a 37-kDa protein band in Mito; angiotensinogen (Aogen) conversion was abolished by the inhibitor aliskiren. Mito Aogen was detected by an Aogen antibody to an internal sequence of the protein, but not with an antibody directed against the ANG I N terminus. ANG peptides were quantified by three direct RIAs; mitochondrial ANG II and ANG-(1–7) contents were higher compared with ANG I (23 ± 8 and 58 ± 17 vs. 2 ± 1 fmol/mg protein; P < 0.01, n = 3). 125I-ANG I metabolism primarily revealed the formation of 125I-ANG-(1–7) in Mito that reflects the endopeptidases neprilysin and thimet oligopeptidase. Last, immunoblot studies utilizing the ANG-(1–7)/Mas receptor antibody revealed the protein in isolated Mito from sheep renal cortex. Collectively, the current data demonstrate that Mito actively metabolize the RAS precursor protein Aogen, suggesting that ANG-(1–7) may be generated within Mito to establish an intramitochondrial RAS tone and contribute to renal mitochondrial function.
Repetition suppression for visual actions in the macaque superior temporal sulcus
Authors: Kuravi Pradeep , Caggiano Vittorio , Giese Martin , Vogels Rufin
Published: December 2015

In many brain areas, repetition of a stimulus usually weakens the neural response. This “adaptation” or repetition suppression effect has been observed with mass potential measures such as event-related potentials (ERPs), in fMRI BOLD responses, and locally with local field potentials (LFPs) and spiking activity. Recently, it has been reported that macaque F5 mirror neurons do not show repetition suppression of their spiking activity for single repetitions of hand actions, which disagrees with human fMRI adaptation studies. This finding also contrasts with numerous studies showing repetition suppression in macaque inferior temporal cortex, including the rostral superior temporal sulcus (STS). Since the latter studies employed static stimuli, we assessed here whether the use of dynamic action stimuli abolishes repetition suppression in the awake macaque STS. To assess adaptation effects in the STS, we employed the same hand action movies as used when examining adaptation in F5. The upper bank STS neurons showed repetition suppression during the approaching phase of the hand action, which corresponded to the phase of the action for which these neurons responded overall the strongest. The repetition suppression was present for the spiking activity measured in independent single-unit and multiunit recordings as well as for the LFP power at frequencies > 50 Hz. Together with previous data in F5, these findings suggest that adaptation effects differ between F5 mirror neurons and the STS neurons.
Trunk stabilization during sagittal pelvic tilt: from trunk-on-pelvis to trunk-in-space due to vestibular and visual feedback
Authors: van Drunen Paul , van der Helm Frans C. T. , van Dieën Jaap H. , Happee Riender
Published: December 2015

The goal of this study was to investigate the human ability to stabilize the trunk in space during pelvic tilt. Upper body sway was evoked in kneeling-seated healthy subjects by angular platform perturbations with a rotation around a virtual low-back pivot point between the L4 and L5 vertebrae. To investigate motor control modulation, variations in task instruction (balance naturally or minimize trunk sway), vision (eyes open or closed), and perturbation bandwidth (from 0.2 up to 1, 3, or 10 Hz) were applied. Cocontraction and proprioceptive muscle spindle feedback were associated with minimizing low-back flexion/extension (trunk-on-pelvis stabilization), while vestibular and visual feedback were supposed to contribute to trunk-in-space stabilization. Trunk-in-space stabilization was only observed with the minimize trunk sway task instruction, while the task instruction to balance naturally led to trunk-on-pelvis stabilization with trunk rotations even exceeding the perturbations. This indicates that vestibular feedback is used when minimizing trunk sway but has only a minor contribution during natural trunk stabilization in the sagittal plane. The eyes open condition resulted in reduced global trunk rotations and increased global trunk reflexive responses, demonstrating effective visual contributions to trunk-in-space stabilization. On the other hand, increasing perturbation bandwidth caused a decreased feedback contribution leading to deteriorated trunk-in-space stabilization.
Dissociable saccadic suppression of pupillary and perceptual responses to light
Authors: Benedetto Alessandro , Binda Paola
Published: December 2015

We measured pupillary constrictions in response to full-screen flashes of variable luminance, occurring either at the onset of a saccadic eye movement or well before/after it. A large fraction of perisaccadic flashes were undetectable to the subjects, consistent with saccadic suppression of visual sensitivity. Likewise, pupillary responses to perisaccadic flashes were strongly suppressed. However, the two phenomena appear to be dissociable. Across subjects and luminance levels of the flash stimulus, there were cases in which conscious perception of the flash was completely depleted yet the pupillary response was clearly present, as well as cases in which the opposite occurred. On one hand, the fact that pupillary light responses are subject to saccadic suppression reinforces evidence that this is not a simple reflex but depends on the integration of retinal illumination with complex “extraretinal” cues. On the other hand, the relative independence of pupillary and perceptual responses suggests that suppression acts separately on these systems—consistent with the idea of multiple visual pathways that are differentially affected by saccades.
Na/K-ATPase signaling regulates collagen synthesis through microRNA-29b-3p in cardiac fibroblasts
Authors: Drummond Christopher A. , Hill Michael C. , Shi Huilin , Fan Xiaoming , Xie Jeffrey X. , Haller Steven T. , Kennedy David J. , Liu Jiang , Garrett Michael R. , Xie Zijian , Cooper Christopher J. , Shapiro Joseph I. , Tian Jiang
Published: December 2015

Chronic kidney disease (CKD) is accompanied by cardiac fibrosis, hypertrophy, and dysfunction, which are commonly referred to as uremic cardiomyopathy. Our previous studies found that Na/K-ATPase ligands or 5/6th partial nephrectomy (PNx) induces cardiac fibrosis in rats and mice. The current study used in vitro and in vivo models to explore novel roles for microRNA in this mechanism of cardiac fibrosis formation. To accomplish this, we performed microRNA profiling with RT-qPCR based arrays on cardiac tissue from rats subjected to marinobufagenin (MBG) infusion or PNx. The analysis showed that a series of fibrosis-related microRNAs were dysregulated. Among the dysregulated microRNAs, microRNA (miR)-29b-3p, which directly targets mRNA of collagen, was consistently reduced in both PNx and MBG-infused animals. In vitro experiments demonstrated that treatment of primary cultures of adult rat cardiac fibroblasts with Na/K-ATPase ligands induced significant increases in the fibrosis marker, collagen protein, and mRNA expression compared with controls, whereas miR-29b-3p expression decreased >50%. Transfection of miR-29b-3p mimics into cardiac fibroblasts inhibited cardiotonic steroids-induced collagen synthesis. Moreover, a specific Na/K-ATPase signaling antagonist, pNaKtide, prevented ouabain-induced increases in collagen synthesis and decreases in miR-29b-3p expression in these cells. In conclusion, these data are the first to indicate that signaling through Na/K-ATPase regulates miRNAs and specifically, miR-29b-3p expression both in vivo and in vitro. Additionally, these data indicate that miR-29b-3p expression plays an important role in the formation of cardiac fibrosis in CKD.
Efavirenz Induced Suicidal Death of Human Erythrocytes
Authors: Bissinger Rosi , Bouguerra Ghada , Al Mamun Bhuyan Abdulla , Waibel Sabrina , Abbès Salem , Lang Florian
Published: December 2015

Background/Aims: The reverse transcriptase inhibitor efavirenz utilized for the treatment of human immunodeficiency virus (HIV)-1 infection, triggers suicidal cell death or apoptosis, an effect in part due to interference with mitochondrial potential. Side effects of efavirenz include anemia. Causes of anemia include accelerated clearance of circulating erythrocytes. Even though lacking mitochondria, erythrocytes may enter suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include Ca2+ entry and increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, ceramide, as well as activation of p38 kinase, casein kinase 1α and/or cyclooxygenase. The present study explored, whether and how efavirenz induces eryptosis. Methods: Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence, and ceramide abundance utilizing selective antibodies. Results: A 48 hours exposure of human erythrocytes to efavirenz (≥ 2 µg/ml) significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter (2 µg/ml), significantly increased Fluo3-fluorescence (≥ 2 µg/ml), but did not significantly modify DCFDA fluorescence or ceramide abundance. The effect of efavirenz on annexin-V-binding was significantly blunted, but not abolished by removal of extracellular Ca2+. The effect of efavirenz on annexin-V-binding was further significantly blunted by p38 kinase inhibitor SB203580 (2 µM) and casein kinase 1α inhibitor D4476 (10 µM), but not by cyclooxygenase inhibitor aspirin (50 µM). Conclusions: Efavirenz triggers cell shrinkage and phosphatidylserine translocation to the erythrocyte surface, an effect in part due to stimulation of Ca2+ entry as well as activation of p38 kinase and casein kinase 1α.
Recurrent Episodes of Stroke-Like Symptoms in a Patient with Charcot-Marie-Tooth Neuropathy X Type 1
Authors: Wu Ning , Said Sarita , Sabat Shyamsunder , Wicklund Matthew , Stahl Mark C.
Published: December 2015

Charcot-Marie-Tooth disease (CMT), also known as hereditary motor sensory neuropathy, is a heterogeneous group of disorders best known for causing inherited forms of peripheral neuropathy. The X-linked form, CMTX1, is caused by mutations in the gap junction protein beta 1 (GJB1) gene, expressed both by peripheral Schwann cells and central oligodendrocytes. Central manifestations are known but are rare, and there are few case reports of leukoencephalopathy with transient or persistent neurological deficits in patients with this CMT subtype. Here, we report the case of a man with multiple male and female family members affected by neuropathy who carries a pathologic mutation in GJB1. He has experienced three transient episodes with variable neurological deficits over the course of 7 years with corresponding changes on magnetic resonance imaging (MRI). This case illustrates CMT1X as a rare cause of transient neurological deficit and demonstrates the evolution of associated reversible abnormalities on MRI over time. To the best of our knowledge, this report provides the longest period of serial imaging in a single patient with this condition in the English language literature.
James Wood’s Rogósânti: aspects of the analysis in a first approach
Authors: Sulpicio Eliana C. M. G. , Bologna Ricardo
Published: December 2015

O presente artigo apresenta algumas considerações iniciais a respeito da peça Rogósânti de James Wood. Escrita em 1986 para múltipla percussão e dedicada ao percussionista Steven Schick, esta peça se configura em um grande “percurso tripartido”, onde o compositor apresenta dois motivos principais baseados em células rítmicas da música indiana. Nesta primeira etapa da análise apresentamos algumas hipóteses relativa a uma possível “inspiração” ligada ao conceito de personagens rítmicos de Oliver Messiaen.