bluuebunny/crossref_metadata_2025 huggingface dataset:
A Linear-Size Logarithmic Stretch Path-Reporting Distance Oracle for General Graphs
Authors: Elkin Michael , Pettie Seth
Published: August 2016

Thorup and Zwick [2001a] proposed a landmark distance oracle with the following properties. Given an
n
-vertex undirected graph
G
= (
V
,
E
) and a parameter
k
= 1, 2, …, their oracle has size
O
(
kn

1 + 1/
k

), and upon a query (
u
,
v
) it constructs a path Π between
u
and
v
of length δ(
u
,
v
) such that

d
G

(
u
,
v
) ⩽ δ(
u
,
v
) ⩽ (2
k
− 1)

d
G

(
u
,
v
). The query time of the oracle from Thorup and Zwick [2001a] is
O
(
k
) (in addition to the length of the returned path), and it was subsequently improved to
O
(1) [Wulff-Nilsen 2012; Chechik 2014]. A major drawback of the oracle of Thorup and Zwick [2001a] is that its space is Ω(
n
· log
n
). Mendel and Naor [2006] devised an oracle with space
O
(
n

1 + 1/
k

) and stretch
O
(
k
), but their oracle can only report distance estimates and not actual paths. In this article, we devise a path-reporting distance oracle with size
O
(
n

1 + 1/
k

), stretch
O
(
k
), and query time
O
(
n
ϵ
), for an arbitrarily small constant ϵ > 0. In particular, for
k
= log
n
, our oracle provides logarithmic stretch using linear size. Another variant of our oracle has size
O
(
n
loglog
n
), polylogarithmic stretch, and query time
O
(loglog
n
).

For unweighted graphs, we devise a distance oracle with multiplicative stretch
O
(1), additive stretch
O
(β(
k
)), for a function β(·), space
O
(
n

1 + 1/
k

), and query time
O
(
n
ϵ
), for an arbitrarily small constant ϵ > 0. The tradeoff between multiplicative stretch and size in these oracles is far below Erdős’s girth conjecture threshold (which is stretch 2
k
− 1 and size
O
(
n

1 + 1/
k

)). Breaking the girth conjecture tradeoff is achieved by exhibiting a tradeoff of different nature between additive stretch β(
k
) and size
O
(
n

1 + 1/
k

). A similar type of tradeoff was exhibited by a construction of (1 + ϵ, β)-spanners due to Elkin and Peleg [2001]. However, so far (1 + ϵ, β)-spanners had no counterpart in the distance oracles’ world.

An important novel tool that we develop on the way to these results is a distance-preserving path-reporting oracle. We believe that this oracle is of independent interest.
Persistent Clocks for Batteryless Sensing Devices
Authors: Hester Josiah , Tobias Nicole , Rahmati Amir , Sitanayah Lanny , Holcomb Daniel , Fu Kevin , Burleson Wayne P. , Sorber Jacob
Published: August 2016

Sensing platforms are becoming batteryless to enable the vision of the Internet of Things, where trillions of devices collect data, interact with each other, and interact with people. However, these batteryless sensing platforms—that rely purely on energy harvesting—are rarely able to maintain a sense of time after a power failure. This makes working with sensor data that is time sensitive especially difficult. We propose two novel, zero-power timekeepers that use remanence decay to measure the time elapsed between power failures. Our approaches compute the elapsed time from the amount of decay of a capacitive device, either on-chip Static Random-Access Memory (SRAM) or a dedicated capacitor. This enables hourglass-like timers that give intermittently powered sensing devices a persistent sense of time. Our evaluation shows that applications using either timekeeper can keep time accurately through power failures as long as 45s with low overhead.
Compressed Cache-Oblivious String B-Tree
Authors: Ferragina Paolo , Venturini Rossano
Published: August 2016

In this article, we study three variants of the well-known prefix-search problem for strings, and we design solutions for the cache-oblivious model which improve the best known results. Among these contributions, we close (asymptotically) the classic problem, which asks for the detection of the set of strings that share the longest common prefix with a queried pattern by providing an I/O-optimal solution that matches the space lower bound for tries up to a constant multiplicative factor of the form (1 + ϵ), for ϵ > 0. Our solutions hinge upon a novel compressed storage scheme that adds the ability to decompress
prefixes
of the stored strings I/O-optimally to the elegant locality-preserving front coding (Bender et al. 2006) still preserving its space bounds.
PEAS
Authors: Papadopoulos Alessandro Vittorio , Ali-Eldin Ahmed , Årzén Karl-Erik , Tordsson Johan , Elmroth Erik
Published: August 2016

Numerous auto-scaling strategies have been proposed in the past few years for improving various Quality of Service (QoS) indicators of cloud applications, for example, response time and throughput, by adapting the amount of resources assigned to the application to meet the workload demand. However, the evaluation of a proposed auto-scaler is usually achieved through experiments under specific conditions and seldom includes extensive testing to account for uncertainties in the workloads and unexpected behaviors of the system. These tests by no means can provide guarantees about the behavior of the system in general conditions. In this article, we present a Performance Evaluation framework for Auto-Scaling (PEAS) strategies in the presence of uncertainties. The evaluation is formulated as a
chance constrained optimization problem
, which is solved using
scenario theory
. The adoption of such a technique allows one to give probabilistic guarantees of the obtainable performance. Six different auto-scaling strategies have been selected from the literature for extensive test evaluation and compared using the proposed framework. We build a discrete event simulator and parameterize it based on real experiments. Using the simulator, each auto-scaler’s performance is evaluated using 796 distinct real workload traces from projects hosted on the Wikimedia foundations’ servers, and their performance is compared using PEAS. The evaluation is carried out using different performance metrics, highlighting the flexibility of the framework, while providing probabilistic bounds on the evaluation and the performance of the algorithms. Our results highlight the problem of generalizing the conclusions of the original published studies and show that based on the evaluation criteria, a controller can be shown to be better than other controllers.
On the Improved Hard Real-Time Scheduling of Cyclo-Static Dataflow
Authors: Spasic Jelena , Liu Di , Cannella Emanuele , Stefanov Todor
Published: August 2016

Recently, it has been shown that the hard real-time scheduling theory can be applied to streaming applications modeled as acyclic Cyclo-Static Dataflow (CSDF) graphs. However, this recent approach is not always efficient in terms of throughput and processor utilization. Therefore, in this article, we propose an improved hard real-time scheduling approach to schedule streaming applications modeled as acyclic CSDF graphs on a Multiprocessor System-on-Chip (MPSoC) platform. The proposed approach converts each actor in a CSDF graph to a set of real-time periodic tasks. The conversion enables application of many hard real-time scheduling algorithms that offer fast calculation of the required number of processors for scheduling the tasks. In addition, we propose a method to reduce the graph latency when the converted tasks are scheduled as real-time periodic tasks. We evaluate the performance and time complexity of our approach in comparison to several existing scheduling approaches. Experiments on a set of real-life streaming applications demonstrate that our approach (1) results in systems with higher throughput and better processor utilization in comparison to the existing hard real-time scheduling approach for CSDF graphs, while requiring comparable time for the system derivation; (2) delivers shorter application latency by applying the proposed method for graph latency reduction while providing better throughput and processor utilization when compared to the existing hard real-time scheduling approach; (3) gives the same throughput as the existing periodic scheduling approach for CSDF graphs, but requires much shorter time to derive the task schedule and tasks’ parameters (periods, start times, and so on); and (4) gives the throughput that is equal to or very close to the maximum achievable throughput of an application obtained via self-timed scheduling, but requires much shorter time to derive the schedule. The total time needed for the proposed conversion approach and the calculation of the minimum number of processors needed to schedule the tasks and the calculation of the size of communication buffers between tasks is in the range of seconds.
Parallel Peeling Algorithms
Authors: Jiang Jiayang , Mitzenmacher Michael , Thaler Justin
Published: August 2016

The analysis of several algorithms and data structures can be framed as a
peeling process
on a random hypergraph: vertices with degree less than
k
are removed until there are no vertices of degree less than
k
left. The remaining hypergraph is known as the
k
-core. In this article, we analyze parallel peeling processes, in which in each round, all vertices of degree less than
k
are removed. It is known that, below a specific edge-density threshold, the
k
-core is empty with high probability. We show that, with high probability, below this threshold, only 1/log((
k
-1)(
r
-1)) log log
n
+
O
(1) rounds of peeling are needed to obtain the empty
k
-core for
r
-uniform hypergraphs. This bound is tight up to an additive constant. Interestingly, we show that, above this threshold, Ω(log
n
) rounds of peeling are required to find the nonempty
k
-core. Since most algorithms and data structures aim to peel to an empty
k
-core, this asymmetry appears fortunate. We verify the theoretical results both with simulation and with a parallel implementation using graphics processing units (GPUs). Our implementation provides insights into how to structure parallel peeling algorithms for efficiency in practice.
Beyond the Touchscreen
Authors: Zhang Cheng , Guo Anhong , Zhang Dingtian , Li Yang , Southern Caleb , Arriaga Rosa I. , Abowd Gregory D.
Published: August 2016

Most smartphones today have a rich set of sensors that could be used to infer input (e.g., accelerometer, gyroscope, microphone); however, the primary mode of interaction is still limited to the front-facing touchscreen and several physical buttons on the case. To investigate the potential opportunities for interactions supported by built-in sensors, we present the implementation and evaluation of BeyondTouch, a family of interactions to extend and enrich the input experience of a smartphone. Using only existing sensing capabilities on a commodity smartphone, we offer the user a wide variety of additional inputs on the case and the surface adjacent to the smartphone. Although most of these interactions are implemented with machine learning methods, compact and robust rule-based detection methods can also be applied for recognizing some interactions by analyzing physical characteristics of tapping events on the phone. This article is an extended version of Zhang et al. [2015], which solely covered gestures implemented by machine learning methods. We extended our previous work by adding gestures implemented with rule-based methods, which works well with different users across devices without collecting any training data. We outline the implementation of both machine learning and rule-based methods for these interaction techniques and demonstrate empirical evidence of their effectiveness and usability. We also discuss the practicality of BeyondTouch for a variety of application scenarios and compare the two different implementation methods.
Depth-Based View-Invariant Blind 3D Image Watermarking
Authors: Rana Shuvendu , Sur Arijit
Published: August 2016

With the huge advance in Internet technology as well as the availability of low-cost 3D display devices, 3D image transmission has become popular in recent times. Since watermarking has become regarded as a potential Digital Rights Management (DRM) tools in the past decade, 3D image watermarking is an emerging research topic. With the introduction of the Depth Image-Based Rendering (DIBR) technique, 3D image watermarking is a more challenging task, especially for synthetic view generation. In this article, synthetic view generation is regarded as a potential attack, and a blind watermarking scheme is proposed that can resist it. In the proposed scheme, the watermark is embedded into the low-pass filtered dependent view region of 3D images. Block Discrete Cosine Transformation (DCT) is used for spatial-filtration of the dependent view region to find the DC coefficient with horizontally shifted coherent regions from the left and right view to make the scheme robust against synthesis view attack. A comprehensive set of experiments have been carried out to justify the robustness of the proposed scheme over related existing schemes with respect to Stereo JPEG compression and different noise addition attacks.
Insulin and SGK1 reduce the function of Na+/monocarboxylate transporter 1 (SMCT1/SLC5A8)
Authors: López-Barradas Adriana , González-Cid Tania , Vázquez Norma , Gavi-Maza Marisol , Reyes-Camacho Adriana , Velázquez-Villegas Laura A. , Ramírez Victoria , Zandi-Nejad Kambiz , Mount David B. , Torres Nimbe , Tovar Armando R. , Romero Michael F. , Gamba Gerardo , Plata Consuelo
Published: August 2016

SMCTs move several important fuel molecules that are involved in lipid, carbohydrate, and amino acid metabolism, but their regulation has been poorly studied. Insulin controls the translocation of several solutes that are involved in energetic cellular metabolism, including glucose. We studied the effect of insulin on the function of human SMCT1 expressed in Xenopus oocytes. The addition of insulin reduced α-keto-isocaproate (KIC)-dependent 22Na+ uptake by 29%. Consistent with this result, the coinjection of SMCT1 with SGK1 cRNA decreased the KIC-dependent 22Na+ uptake by 34%. The reduction of SMCT1 activity by SGK1 depends on its kinase activity, and it was observed that the coinjection of SMCT1 with S442D-SGK1 (a constitutively active mutant) decreased the KIC-dependent 22Na+ uptake by 50%. In contrast, an SMCT1 coinjection with K127M-SGK1 (an inactive mutant) had no effect on the KIC-dependent Na+ uptake. The decreasing SMCT1 function by insulin or SGK1 was corroborated by measuring [1-14C]acetate uptake and the electric currents of SMCT1-injected oocytes. Previously, we found that SMCT2/Slc5a12-mRNA, but not SMCT1/Slc5a8-mRNA, is present in zebrafish pancreas (by in situ hybridization); however, SLC5a8 gene silencing was associated with the development of human pancreatic cancer. We confirmed that the mRNA and protein of both transporters were present in rat pancreas using RT-PCR with specific primers, Western blot analysis, and immunohistochemistry. Additionally, significant propionate-dependent 22Na+ uptake occurred in pancreatic islets and was reduced by insulin treatment. Our data indicate that human SMCT1 is regulated by insulin and SGK1 and that both SMCTs are present in the mammalian pancreas.
Postsynaptic nicotinic acetylcholine receptors facilitate excitation of developing CA1 pyramidal neurons
Authors: Chung Beryl Y. T. , Bignell Warren , Jacklin Derek L. , Winters Boyer D. , Bailey Craig D. C.
Published: August 2016

The hippocampus plays a key role in learning and memory. The normal development and mature function of hippocampal networks supporting these cognitive functions depends on afferent cholinergic neurotransmission mediated by nicotinic acetylcholine receptors. Whereas it is well-established that nicotinic receptors are present on GABAergic interneurons and on glutamatergic presynaptic terminals within the hippocampus, the ability of these receptors to mediate postsynaptic signaling in pyramidal neurons is not well understood. We use whole cell electrophysiology to show that heteromeric nicotinic receptors mediate direct inward currents, depolarization from rest and enhanced excitability in hippocampus CA1 pyramidal neurons of male mice. Measurements made throughout postnatal development provide a thorough developmental profile for these heteromeric nicotinic responses, which are greatest during the first 2 wk of postnatal life and decrease to low adult levels shortly thereafter. Pharmacological experiments show that responses are blocked by a competitive antagonist of α4β2* nicotinic receptors and augmented by a positive allosteric modulator of α5 subunit-containing receptors, which is consistent with expression studies suggesting the presence of α4β2 and α4β2α5 nicotinic receptors within the developing CA1 pyramidal cell layer. These findings demonstrate that functional heteromeric nicotinic receptors are present on CA1 pyramidal neurons during a period of major hippocampal development, placing these receptors in a prime position to play an important role in the establishment of hippocampal cognitive networks.
A Single Mass Forming Colonic Primary Mantle Cell Lymphoma
Authors: Daniel Fady , Assi Hazem I. , Karaoui Walid , El Cheikh Jean , Bannoura Sami , Nassif Samer
Published: August 2016

Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin’s lymphoma (NHL) comprising around 7% of adult NHL. It is characterized by a chromosomal translocation t(11:14) and overexpression of Cyclin D1. The incidence of secondary gastrointestinal tract involvement in MCL ranges from 10 to 28% in various series. However primary gastrointestinal MCL is very rare, accounting for only 1 to 4% of primary gastrointestinal lymphomas. The most common endoscopic feature of primary intestinal MCL is multiple lymphomatous polyposis. In rare cases it presents as protruded lesions or superficial lesions. Single colonic mass presentation is an extremely infrequent presentation. MCL has an aggressive course with quick progression, and most cases are discovered in the advanced stages. Colonic biopsies with histologic examination and specific immunohistochemical staining are the gold standard for a proper diagnosis. We report a case of a single mass forming mantle cell lymphoma of the ascending colon in a 57-year-old female patient with unusual colonoscopic and radiologic features and describe the therapy the patient received, thereby adding to the spectrum of clinical presentations of this aggressive lymphoproliferative disorder.
Association of Immunosuppression with DR6 Expression during the Development and Progression of Spontaneous Ovarian Cancer in Laying Hen Model
Authors: McNeal Sa’Rah , Bitterman Pincas , Bahr Janice M. , Edassery Seby L. , Abramowicz Jacques S. , Basu Sanjib , Barua Animesh
Published: August 2016

Ovarian cancer (OVCA) mainly disseminates in the peritoneal cavity. Immune functions are important to prevent OVCA progression and recurrence. The mechanism of immunosuppression, a hallmark of tumor progression, is not well understood. The goal of this study was to determine the immune system’s responses and its suppression during OVCA development and progression in hens. Frequencies of CD8+ T cells and IgY-containing cells and expression of immunosuppressors including IRG1 and DR6 in OVCA at early and late stages in hens were examined. Frequencies of stromal but not the intratumoral CD+8 T cells and IgY-containing cells increased significantly (P<0.01) during OVCA development and progression. Tumor progression was associated with increased expression of IRG1 and DR6 and decreased infiltration of immune cells into the tumor. Frequency of stromal but not intratumoral immune cells increases during OVCA development and progression. Tumor-induced IRG1 and DR6 may prevent immune cells from invading the tumor.
Technoeconomical Analysis of Macrocell and Femtocell Based HetNet under Different Deployment Constraints
Authors: Yunas Syed Fahad , Ansari Waqas H. , Valkama Mikko
Published: August 2016

Ultradense deployment of small cells is being considered as one of the key flavors of the emerging 5G cellular networks to address the future data capacity challenges. A large share of these deployments will be indoor, as this is the arena where the majority of the data traffic is believed to originate from in the future. Indoor small cell solutions (e.g., femtocell or WiFi) are well positioned for delivering superior indoor coverage and capacity. However, due to relatively smaller coverage footprint compared to traditional macrocells, a very dense deployment of small cells will be needed in order to have a ubiquitous indoor coverage. Such dense deployment triggers cost and energy efficiency concerns for mobile operators. In this paper, we analyze and compare the technoeconomic performance of two deployment strategies: homogeneous macrocellular densification and heterogeneous macro-femto deployment strategy, from an indoor service provisioning perspective. Particularly, we analyze and contrast the performance of macro-femto based deployment, with varying femtocell market penetration rate and under different femtocell backhaul connectivity constraints, with that of homogeneous macrocellular densification. The results indicate superior performance of indoor femtocell based deployment as compared to macrocellular-only densification, due to better indoor coverage, radio channel conditions, and high degree of spatial reuse.
Lower Limb Loading during Gait in Patients Long Period after Total Hip Arthroplasty Revision
Authors: Kubonova Eliska , Svoboda Zdenek , Janura Miroslav , Gallo Jiri , Duskova Sarka
Published: August 2016

The aim of the study was to assess lower limb loading during walking after unilateral total hip arthroplasty (THA) revision. Twenty-three THA revision subjects (12 men, 11 women) were divided into three groups according to time since surgery as 1 to 6 years, 6 to 11 years, and over 11 years. Two force plates were used to measure the ground reaction force during the stance phase. On the operated limb, compared to nonoperated limb, we found lower first vertical peak in the group of 1 to 6 years after revision and lower propulsion peak in the group of 6 to 11 years since revision. In the group of 11 years since THA revision, no significant difference was found. With advancing years after surgery, the stance phase duration got reduced and propulsion peak increased in the operated limb; minimal vertical force decreased and the time of minimal vertical force increased in the nonoperated limb. The study findings suggest the tendency to a more gradual and safer weight acceptance on the operated limb during the first years after THA revision, followed by limitation of foot propulsion. Despite this fact, lower limb loading can be considered as symmetrical across the whole measured period.
Original Framework for Optimizing Hybrid Energy Supply
Authors: Acakpovi Amevi
Published: August 2016

This paper proposes an original framework for optimizing hybrid energy systems. The recent growth of hybrid energy systems in remote areas across the world added to the increasing cost of renewable energy has triggered the inevitable development of hybrid energy systems. Hybrid energy systems always pose a problem of optimization of cost which has been approached with different perspectives in the recent past. This paper proposes a framework to guide the techniques of optimizing hybrid energy systems in general. The proposed framework comprises four stages including identification of input variables for energy generation, establishment of models of energy generation by individual sources, development of artificial intelligence, and finally summation of selected sources. A case study of a solar, wind, and hydro hybrid system was undertaken with a linear programming approach. Substantial results were obtained with regard to how load requests were constantly satisfied while minimizing the cost of electricity. The developed framework gained its originality from the fact that it has included models of individual sources of energy that even make the optimization problem more complex. This paper also has impacts on the development of policies which will encourage the integration and development of renewable energies.
Prenatal Diagnosis of Isolated Agnathia-Otocephaly: A Case Report and Review of the Literature
Authors: Kajiwara Kazuhiro , Tanemoto Tomohiro , Nagata Chie , Okamoto Aikou
Published: August 2016

Agnathia is a rare disease characterized by the absence of a mandible. Few cases of prenatally diagnosed isolated agnathia have been reported. We present a case report and review of the literature of prenatally diagnosed agnathia. A 38-year-old woman (gravida 0, para 0) was referred to our hospital at 28 weeks and 3 days of gestation for fetal evaluation because of polyhydramnios and suspected facial anomalies. Three-dimensional ultrasonography and MRI indicated agnathia. Premature rupture of the membranes occurred before the parents could reach a decision on the postnatal treatment. We performed emergency cesarean section on the second day of the 33rd week of gestation. The neonate was deemed nonresuscitable and he died of airway obstruction shortly after birth. Because agnathia is associated with very poor prognosis, accurate prenatal diagnosis and detailed counseling should be promptly provided before unexpected delivery to the parents for the determination of postnatal treatment.
Effect of Endomorphins on HUVECs Treated by ox-LDL and Its Related Mechanisms
Authors: Zhao Juan , Zhang Qi , Liu Jing , Tian Liming , Huang Wenhui , Quan Jinxing , Wang Jinyang , Xu Yanjia , Wang Yunfang , Niu Ruilan
Published: August 2016

We found in the present study that treatment with ox-LDL decreased the cell viability and the content of nitric oxide (NO) and the activity of nitric oxide synthase (NOS) as well as eNOS mRNA expression, while increasing the mRNA expression and content of endothelin-1 (ET-1) in human umbilical vein endothelial cells (HUVECs). However, endomorphins EM1/EM2 increased the cell viability and the content of NO and the activity of NOS as well as eNOS mRNA expression, while decreasing the mRNA expression and content of ET-1 compared with ox-LDL alone. Meanwhile, the expressions of JNK and p-JNK were enhanced by ox-LDL while being suppressed by EM1/EM2. The results suggested that EM1 and EM2 can correct the endothelial cell dysfunction induced by ox-LDL and the protective effect may be achieved by affecting the JNK pathway.
Exercise and Prognosis on the Basis of Clinicopathologic and Molecular Features in Early-Stage Breast Cancer: The LACE and Pathways Studies
Authors: Jones Lee W. , Kwan Marilyn L. , Weltzien Erin , Chandarlapaty Sarat , Sternfeld Barbara , Sweeney Carol , Bernard Philip S. , Castillo Adrienne , Habel Laurel A. , Kroenke Candyce H. , Langholz Bryan M. , Queensberry Charles P. , Dang Chau , Weigelt Britta , Kushi Lawrence H. , Caan Bette J.
Published: August 2016

To investigate whether the impact of postdiagnosis exercise on breast cancer outcomes in women diagnosed with early-stage breast cancer differs on the basis of tumor clinicopathologic and molecular features. Using a prospective design, 6,211 patients with early-stage breast cancer from two large population-based cohort studies were studied. Age-adjusted and multivariable Cox regression models were performed to determine the relationship between exercise exposure (total MET-hours/week) and recurrence and breast cancer–related death for: (i) all patients (“unselected” cohort), and on the basis of (ii) classic clinicopathologic features, (iii) clinical subtypes, (iv) PAM50-based molecular intrinsic subtypes, and (v) individual PAM50 target genes. After a median follow-up of 7.2 years, in the unselected cohort (n = 6,211) increasing exercise exposure was not associated with a reduction in the risk of recurrence (adjusted Ptrend = 0.60) or breast cancer–related death (adjusted Ptrend = 0.39). On the basis of clinicopathologic features, an exercise-associated reduction in breast cancer–related death was apparent for tumors <2 cm [HR, 0.50; 95% confidence interval (CI), 0.34–0.72], well/moderately differentiated tumors (HR, 0.63; 95% CI, 0.43–0.91), and ER-positive tumors (HR, 0.72; 95% CI, 0.53–0.97). Stratification by clinical subtype indicated that the ER+/PR+/HER2−/low-grade clinical subtype was preferentially responsive to exercise (recurrence: adjusted HR, 0.63; 95% CI, 0.45–0.88; breast cancer–related death: adjusted HR, 0.57; 95% CI, 0.37–0.86). The impact of exercise on cancer outcomes appears to differ as a function of pathologic and molecular features in early-stage breast cancer. Cancer Res; 76(18); 5415–22. ©2016 AACR.
In Vivo FRET Imaging of Tumor Endothelial Cells Highlights a Role of Low PKA Activity in Vascular Hyperpermeability
Authors: Yamauchi Fumio , Kamioka Yuji , Yano Tetsuya , Matsuda Michiyuki
Published: August 2016

Vascular hyperpermeability is a pathological hallmark of cancer. Previous in vitro studies have elucidated roles of various signaling molecules in vascular hyperpermeability; however, the activities of such signaling molecules have not been examined in live tumor tissues for technical reasons. Here, by in vivo two-photon excitation microscopy with transgenic mice expressing biosensors based on Förster resonance energy transfer, we examined the activity of protein kinase A (PKA), which maintains endothelial barrier function. The level of PKA activity was significantly lower in the intratumoral endothelial cells than the subcutaneous endothelial cells. PKA activation with a cAMP analogue alleviated the tumor vascular hyperpermeability, suggesting that the low PKA activity in the endothelial cells may be responsible for the tumor-tissue hyperpermeability. Because the vascular endothelial growth factor (VEGF) receptor is a canonical inducer of vascular hyperpermeability and a molecular target of anticancer drugs, we examined the causality between VEGF receptor activity and the PKA activity. Motesanib, a kinase inhibitor for VEGF receptor, activated tumor endothelial PKA and reduced the vascular permeability in the tumor. Conversely, subcutaneous injection of VEGF decreased endothelial PKA activity and induced hyperpermeability of subcutaneous blood vessels. Notably, in cultured human umbilical vascular endothelial cells, VEGF activated PKA rather than decreasing its activity, highlighting the remarkable difference between its actions in vitro and in vivo. These data suggested that the VEGF receptor signaling pathway increases vascular permeability, at least in part, by reducing endothelial PKA activity in the live tumor tissue. Cancer Res; 76(18); 5266–76. ©2016 AACR.
Multivalent Peptoid Conjugates Which Overcome Enzalutamide Resistance in Prostate Cancer Cells
Authors: Wang Yu , Dehigaspitiya Dilani C. , Levine Paul M. , Profit Adam A. , Haugbro Michael , Imberg-Kazdan Keren , Logan Susan K. , Kirshenbaum Kent , Garabedian Michael J.
Published: August 2016

Development of resistance to antiandrogens for treating advanced prostate cancer is a growing concern and extends to recently developed therapeutics, including enzalutamide. Therefore, new strategies to block androgen receptor (AR) function in prostate cancer are required. Here, we report the characterization of a multivalent conjugate presenting two bioactive ethisterone ligands arrayed as spatially defined pendant groups on a peptoid oligomer. The conjugate, named Multivalent Peptoid Conjugate 6 (MPC6), suppressed the proliferation of multiple AR-expressing prostate cancer cell lines including those that failed to respond to enzalutamide and ARN509. The structure–activity relationships of MPC6 variants were evaluated, revealing that increased spacing between ethisterone moieties and changes in peptoid topology eliminated its antiproliferative effect, suggesting that both ethisterone ligand presentation and scaffold characteristics contribute to MPC6 activity. Mechanistically, MPC6 blocked AR coactivator–peptide interaction and prevented AR intermolecular interactions. Protease sensitivity assays suggested that the MPC6-bound AR induced a receptor conformation distinct from that of dihydrotestosterone- or enzalutamide-bound AR. Pharmacologic studies revealed that MPC6 was metabolically stable and displayed a low plasma clearance rate. Notably, MPC6 treatment reduced tumor growth and decreased Ki67 and AR expression in mouse xenograft models of enzalutamide-resistant LNCaP-abl cells. Thus, MPC6 represents a new class of compounds with the potential to combat treatment-resistant prostate cancer. Cancer Res; 76(17); 5124–32. ©2016 AACR.
Stimulation of Natural Killer Cell–Mediated Tumor Immunity by an IL15/TGFβ–Neutralizing Fusion Protein
Authors: Ng Spencer , Deng Jiusheng , Chinnadurai Raghavan , Yuan Shala , Pennati Andrea , Galipeau Jacques
Published: August 2016

The clinical efficacy of immune cytokines used for cancer therapy is hampered by elements of the immunosuppressive tumor microenvironment such as TGFβ. Here we demonstrate that FIST15, a recombinant chimeric protein composed of the T-cell–stimulatory cytokine IL15, the sushi domain of IL15Rα and a TGFβ ligand trap, can overcome immunosuppressive TGFβ to effectively stimulate the proliferation and activation of natural killer (NK) and CD8+ T cells with potent antitumor properties. FIST15-treated NK and CD8+ T cells produced more IFNγ and TNFα compared with treatment with IL15 and a commercially available TGFβ receptor-Fc fusion protein (sTβRII) in the presence of TGFβ. Murine B16 melanoma cells, which overproduce TGFβ, were lysed by FIST15-treated NK cells in vitro at doses approximately 10-fold lower than NK cells treated with IL15 and sTβRII. Melanoma cells transduced to express FIST15 failed to establish tumors in vivo in immunocompetent murine hosts and could only form tumors in beige mice lacking NK cells. Mice injected with the same cells were also protected from subsequent challenge by unmodified B16 melanoma cells. Finally, mice with pre-established B16 melanoma tumors responded to FIST15 treatment more strongly compared with tumors treated with control cytokines. Taken together, our results offer a preclinical proof of concept for the use of FIST15 as a new class of biological therapeutics that can coordinately neutralize the effects of immunosuppressive TGFβ in the tumor microenvironment while empowering tumor immunity. Cancer Res; 76(19); 5683–95. ©2016 AACR.
Antihypoxic Potentiation of Standard Therapy for Experimental Colorectal Liver Metastasis through Myo-Inositol Trispyrophosphate
Authors: Limani Perparim , Linecker Michael , Kachaylo Ekaterina , Tschuor Christoph , Kron Philipp , Schlegel Andrea , Ungethuem Udo , Jang Jae Hwi , Georgiopoulou Stavroula , Nicolau Claude , Lehn Jean-Marie , Graf Rolf , Humar Bostjan , Clavien Pierre-Alain
Published: August 2016

Purpose: Tumor hypoxia activates hypoxia-inducible factors (Hifs), which induce a range of malignant changes including vascular abnormalities. Here, we determine whether inhibition of the hypoxic tumor response through myo-inositol trispyrophosphate (ITPP), a compound with antihypoxic properties, is able to cause prolonged vascular normalization that can be exploited to improve standard-of-care treatment.

Experimental Design: We tested ITPP on two syngeneic orthotopic mouse models of lethal colorectal cancer liver metastasis. Tumors were monitored by MRI and analyzed for the hypoxic response and their malignant potential. A Hif activator and in vitro assays were used to define the working mode of ITPP. Hypoxic response and vasculature were re-evaluated 4 weeks after treatment. Finally, we determined survival following ITPP monotherapy, FOLFOX monotherapy, FOLFOX plus Vegf antibody, and FOLFOX plus ITPP, both overlapping and sequential.

Results: ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least 4 weeks after treatment cessation. Compared with FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure.

Conclusions: Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing anticancer treatment in a way amenable to clinical translation. Clin Cancer Res; 22(23); 5887–97. ©2016 AACR.
Dialect Interference in Lexical Processing: Effects of Familiarity and Social Stereotypes
Authors: Clopper Cynthia
Published: August 2016

Background/Aims: The current study explored the roles of dialect familiarityand social stereotypes in dialect interference effects in a speeded lexical classification task. Methods: Listeners classified the words bad and bed or had and head produced by local Midland and non-local Northern talkers and the words sod and side or rod and ride produced by non-local, non-stereotyped Northern and nonlocal, stereotyped Southern talkers in single- and mixed-talker blocks. Results: Lexical classification was better for the local dialect than for the non-local dialects, and for the stereotyped non-local dialect than for the non-stereotyped non-local dialect. Dialect interference effects were observed for all three dialects, although the patterns of interference differed. For the local dialect, dialect interference was observed for response times, whereas for the non-local dialects, dialect interference was observed primarily for accuracy. Conclusion: These findings reveal complex interactions between indexical and lexical information in speech processing.
Dosing of Milrinone in Preterm Neonates to Prevent Postligation Cardiac Syndrome: Simulation Study Suggests Need for Bolus Infusion
Authors: Hallik Maarja , Tasa Tõnis , Starkopf Joel , Metsvaht Tuuli
Published: August 2016

Background: Milrinone has been suggested as a possible first-line therapy for preterm neonates to prevent postligation cardiac syndrome (PLCS) through decreasing systemic vascular resistance and increasing cardiac contractility. The optimal dosing regimen, however, is not known. Objective: To model the dosing of milrinone in preterm infants for prevention of PLCS after surgical closure of patent ductus arteriosus (PDA). Methods: Milrinone time-concentration profiles were simulated for 1,000 subjects using the volume of distribution and clearance estimates based on one compartmental population pharmacokinetic model by Paradisis et al. [Arch Dis Child Fetal Neonatal Ed 2007;92:F204-F209]. Dose optimization was based on retrospectively collected demographic data from neonates undergoing PDA ligation in Estonian PICUs between 2012 and 2014 and existing pharmacodynamic data. The target plasma concentration was set at 150-200 ng/ml. Results: The simulation study used demographic data from 31 neonates who underwent PDA ligation. The median postnatal age was 13 days (range: 3-29) and weight was 760 g (range: 500-2,351). With continuous infusion of milrinone 0.33 μg/kg/min, the proportion of subjects within the desired concentration range was 0% by 3 h, 36% by 6 h, and 61% by 8 h; 99% of subjects exceeded the range by 18 h. The maximum proportion of total simulated concentrations in the target range was attained with a bolus infusion of 0.73 μg/kg/min for 3 h followed by a 0.16-μg/kg/min maintenance infusion. Conclusion: Mathematical simulations suggest that in preterm neonates the plasma time-concentration profile of milrinone can be optimized with a slow loading dose followed by maintenance infusion.
Does Ventriculoperitoneal Shunting Improve Thyroid Hormone Levels in Hydrocephalic Newborns?
Authors: Ucler Necati , Erol Fatih Serhat , Ozturk Sait , Akgun Bekir , Kaplan Metin , Sen Yasar
Published: August 2016

Objective/Aim: The aim of this report was to investigate the effect of ventriculoperitoneal shunt insertion for the treatment of hydrocephalus on thyroid hormones in the first 3 months of life. Methods: Thyroid-stimulating hormone (TSH), free T3 (fT3), and free T4 (fT4) levels were compared at 7 days (preoperatively) and at 30 and 90 days (postoperatively) after birth between 25 ventriculoperitoneal shunt-inserted hydrocephalic newborns and 20 healthy newborns. Results: The TSH level at 7 days was higher in the hydrocephalic patient group (6.33 µIU) compared to the control group (3.76 µIU). This value was significantly decreased at 90 days in the ventriculoperitoneal shunt-inserted newborns (2.35 µIU) compared to the control group (3.33 µIU; p < 0.05). There were no significant differences between time points for fT4 and fT3 values in the patient group or for TSH, fT4, and fT3 values in the control group. Conclusion: We propose that a ventriculoperitoneal shunt inserted in the early period of life may have beneficial effects on thyroid hormones.
Écfrase como exemplo de pintura
Authors: Zanchetta Ricardo
Published: August 2016

Algumas écfrases, que descreveram pinturas dos grandes pintores da antiguidade, como Apeles e Zêuxis, foram lidas e pintadas no século XV. Esse artigo visa mostrar algumas relações entre a pintura e a écfrase, explorando o uso que Leon Battista Alberti faz, em seu Da Pintura, da Calúnia de Apeles descrita por Luciano, elegendo-a como um exemplo de pintura. Tal écfrase não só evidencia os preceitos ensinados, como também impele o pintor a imitar o louvor da pintura antiga.
Odisseia 7.79–135: uma ἔκφρασις
Authors: Martins Paulo
Published: August 2016

Entre as passagens épicas que se valem da écfrase, muito já se discutiu sobre o escudo de Aquiles em Homero, ou o de Héracles em Hesíodo, ou o de Eneias em Virgílio. Também não foram poucos os trabalhos empenhados a discutir as pinturas no templo de Juno em Cartago, apresentadas também na Eneida de Virgílio. Este artigo visa a discutir a écfrase como procedimento retórico-poético aplicado à narrativa da Odisseia, tendo em vista o episódio do palácio de Alcino. Não se preocupa o texto, pois, apenas com os critérios elocutivos da écfrase, como também o trabalha sob uma perspectiva da produção de sentido na narrativa, aproximando o mecanismo ecfrástico do procedimento retórico da digressão.
Ékphrasis no Segundo Comentário de Lorenzo Ghiberti
Authors: Bagolin Luiz Armando
Published: August 2016

Dos três comentários dirigidos por Lorenzo Ghiberti na recolha de autoridades antigas e modernas sobre as artes, o segundo desenvolve cumulativamente uma história das artes de sua idade para a qual o momento áulico é reservado à descrição pormenorizada de suas obras, exempla da arte da escultura entre os florentinos, particularmente os relevos feitos para a Porta do Batistério de Florença.
Normalization of NAD
+
Redox Balance as a Therapy for Heart Failure
Authors: Lee Chi Fung , Chavez Juan D. , Garcia-Menendez Lorena , Choi Yongseon , Roe Nathan D. , Chiao Ying Ann , Edgar John S. , Goo Young Ah , Goodlett David R. , Bruce James E. , Tian Rong
Published: August 2016

Background:

Impairments of mitochondrial function in the heart are linked intricately to the development of heart failure, but there is no therapy for mitochondrial dysfunction.

Methods:

We assessed the reduced/oxidized ratio of nicotinamide adenine dinucleotide (NADH/NAD
+
ratio) and protein acetylation in the failing heart. Proteome and acetylome analyses were followed by docking calculation, mutagenesis, and mitochondrial calcium uptake assays to determine the functional role of specific acetylation sites. The therapeutic effects of normalizing mitochondrial protein acetylation by expanding the NAD
+
pool also were tested.

Results:

Increased NADH/NAD
+
and protein hyperacetylation, previously observed in genetic models of defective mitochondrial function, also are present in human failing hearts as well as in mouse hearts with pathologic hypertrophy. Elevation of NAD
+
levels by stimulating the NAD
+
salvage pathway suppressed mitochondrial protein hyperacetylation and cardiac hypertrophy, and improved cardiac function in responses to stresses. Acetylome analysis identified a subpopulation of mitochondrial proteins that was sensitive to changes in the NADH/NAD
+
ratio. Hyperacetylation of mitochondrial malate-aspartate shuttle proteins impaired the transport and oxidation of cytosolic NADH in the mitochondria, resulting in altered cytosolic redox state and energy deficiency. Furthermore, acetylation of oligomycin-sensitive conferring protein at lysine-70 in adenosine triphosphate synthase complex promoted its interaction with cyclophilin D, and sensitized the opening of mitochondrial permeability transition pore. Both could be alleviated by normalizing the NAD
+
redox balance either genetically or pharmacologically.

Conclusions:

We show that mitochondrial protein hyperacetylation due to NAD
+
redox imbalance contributes to the pathologic remodeling of the heart via 2 distinct mechanisms. Our preclinical data demonstrate a clear benefit of normalizing NADH/NAD
+
imbalance in the failing hearts. These findings have a high translational potential as the pharmacologic strategy of increasing NAD
+
precursors are feasible in humans.
Understanding Orographic Effects on Surface Observations at Macquarie Island
Authors: Wang Zhan , Belusic Danijel , Huang Yi , Siems Steven T. , Manton Michael J.
Published: August 2016

The meteorological observations on Macquarie Island have become of increasing value for efforts to understand the unique nature of atmospheric processes over the Southern Ocean. While the island is of modest elevation (peak altitude of 410 m), the orographic effects on observations on this island are still not clear. High-resolution numerical simulations [Weather Research and Forecasting (WRF) Model] with and without terrain have been used to identify orographic effects for four cases representing common synoptic patterns at Macquarie Island: a cold front, a warm front, postfrontal drizzle, and a midlatitude cyclone. Although the simulations cannot capture every possible feature of the precipitation, preliminary results show that clouds and precipitation can readily be perturbed by the island with the main enhancement of precipitation normally in the lee in accordance with the nondimensional mountain height being much less than 1. The weather station is located at the far north end of the island and is only in the lee to southerly and southwesterly winds, which are normally associated with drizzle. The station is on the upwind side for strong northwesterly winds, which are most common and can bring heavier frontal precipitation. Overall the orographic effect on the precipitation record is not found to be significant, except for the enhancement of drizzle found in southwesterly winds. Given the strong winds over the Southern Ocean and the shallow height of the island, the 3D nondimensional mountain height is smaller than 1 in 93.5% of the soundings. As a result, boundary layer flow commonly passes over the island, with the greatest impact in the lee.
Trends and Variability in Droughts in the Pacific Islands and Northeast Australia
Authors: McGree Simon , Schreider Sergei , Kuleshov Yuriy
Published: August 2016

Drought is a recurrent climate feature of the Pacific Islands and northeast Australia with meteorological and socioeconomic impacts documented from early European settlement. In this study, precipitation records for 21 countries and territories in the Pacific for the period 1951 to 2010 have been examined to identify trends in drought occurrence, duration, and magnitude. The strength of the relationships between the main climate drivers in the Pacific—El Niño–Southern Oscillation (ENSO), the interdecadal Pacific oscillation (IPO), and the Pacific decadal oscillation (PDO)—and precipitation has been also examined. Station-scale drought trends are largely positive, but the majority are statistically nonsignificant with the significant trends mainly in the subtropics. Spatially, trend patterns are largely heterogeneous. A significant relationship between the oceanic component of ENSO and precipitation is confirmed for a large part of the Pacific Islands and eastern Australia with a strong lagged relationship in the year after the El Niño onset at locations southwest of the South Pacific convergence zone (SPCZ) and north of the intertropical convergence zone (ITCZ). Similarly, a strong relationship was found with the IPO and PDO at most locations. Drought was found to be longer and more severe southwest of the SPCZ and north of the ITCZ during the positive phases of the IPO and PDO.