bluuebunny/crossref_metadata_2025 huggingface dataset:
The Instruction-Set Extension Problem
Authors: Galuzzi Carlo , Bertels Koen
Published: June 2011

The extension of a given instruction-set with specialized instructions has become a common technique used to speed up the execution of applications. By identifying computationally intensive portions of an application to be partitioned in segments of code to execute in software and segments of code to execute in hardware, the execution of an application can be considerably speeded up. Each segment of code implemented in hardware can then be seen as a specialized application-specific instruction extending a given instruction-set. Although a number of approaches exist in literature proposing different methodologies to customize an instruction-set, the description of the problem consists only of sporadic comparisons limited to isolated problems. This survey presents a unique detailed description of the problem and provides an exhaustive overview of the research in the past years in instruction-set extension. This article presents a thorough analysis of the issues involved during the customization of an instruction-set by means of a set of specialized application-specific instructions. The investigation of the problem covers both instruction generation and instruction selection and different kinds of customizations are analyzed in a great detail.
Scientific Application Demands on a Reconfigurable Functional Unit Interface
Authors: Rupnow Kyle , Underwood Keith D. , Compton Katherine
Published: June 2011

Modern scientific applications are large, complex, and highly parallel they are commonly executed on supercomputers with tens of thousands of processors. Yet these applications still commonly require weeks or even months to execute. Thus, single-thread performance remains a concern for highly parallel scientific applications. Adding a reconfigurable accelerator to each CPU could improve system performance; however, scientific applications have design constraints that differ from most application domains commonly accelerated by reconfigurable logic. In this article, we discuss the constraints imposed by scientific applications on the computation model, the accelerator architecture, and the accelerator’s communication interface with the CPU. Based on these constraints and application analysis, we have previously proposed adding a Reconfigurable Functional Unit (RFU) to accelerate integer graphs that calculate complex memory addresses. In this work, we now propose a flexible multi-instruction interface technique that allows dataflow graphs implemented on the RFU to access a large number of inputs and outputs with minor CPU datapath modifications. We present an in-depth examination of the performance effects of different communication interfaces that use this technique, and select one that best matches the needs of Sandia’s scientific applications. Although RFU execution overall improves performance, we also isolate two key negative performance effects introduced by aggregating CPU instructions into dataflow graphs: delayed issue and graph serialization. Finally, to demonstrate the marketability of an RFU beyond scientific applications, we reanalyze the proposed interfaces using the SPEC-fp benchmark suite. We show that although choosing an interface based on SPEC-fp needs is detrimental to Sandia application performance, choosing an interface based on Sandia demands works well for more general-purpose applications.
Minimum density RAID-6 codes
Authors: Plank James S. , Buchsbaum Adam L. , Vander Zanden Bradley T.
Published: June 2011

RAID-6 codes protect disk array storage systems from two-disk failures. This article presents a complete treatment of a class of RAID-6 codes, called
minimum density RAID-6 codes
, that have an optimal blend of performance properties. There are two families of minimal density RAID-6 codes: Blaum-Roth codes and Liberation codes, and a separate special-purpose code called the Liber8tion code. The first of these have been known since the late 1990's, while the latter two are new constructions. In this article, we motivate, demonstrate, and evaluate the minimum density codes, comparing them to EVENODD and RDP codes, which represent the state-of-the-art in RAID-6. Following that, we prove that the codes indeed fit the RAID-6 methodology, and cite their implementation in an open-source library.
Estimating PageRank on graph streams
Authors: Sarma Atish Das , Gollapudi Sreenivas , Panigrahy Rina
Published: June 2011

This article focuses on computations on large graphs (e.g., the web-graph) where the edges of the graph are presented as a stream. The objective in the streaming model is to use small amount of memory (preferably sub-linear in the number of nodes
n
) and a smaller number of passes.

In the streaming model, we show how to perform several graph computations including estimating the probability distribution after a random walk of length
l
, the mixing time
M
, and other related quantities such as the conductance of the graph. By applying our algorithm for computing probability distribution on the web-graph, we can estimate the
PageRank
p
of any node up to an additive error of √ε
p
+ε in
Õ
(√
M
/α) passes and
Õ
(min(
n
α+1/ε√
M
/α+(1/ε)
M
α, α
n
√
M
α + (1/ε)√
M
/α)) space, for any α ∈ (0,1]. Specifically, for ε =
M
/
n
, α =
M
−1/2
, we can compute the approximate PageRank values in Õ(
nM
−1/4
) space and Õ(
M
3/4
) passes. In comparison, a standard implementation of the PageRank algorithm will take
O(n)
space and
O(M)
passes. We also give an approach to approximate the PageRank values in just Õ(1) passes although this requires Õ(
nM
) space.
Multitasking, cognitive coordination and cognitive shifts during web searching
Authors: Du Jia Tina
Published: June 2011

Enlightened by the cognitive psychology literature demonstrating that multitasking behavior is correlated closely to humans' cognitive processing and coordinationcapabilities, this doctoral thesis explores the nature and relationship of multitasking, cognitive coordination, and cognitive shifts during Web searching. A combination of data collection techniques including pre- and post-questionnaires, think-aloud protocols, search logs, observations and semi-structured interviews were employed to observe how 42 postgraduate students cognitively coordinated Web searches when multitasking across 126 real-life information problems.

Results show that Web searching is a dynamic interaction between users and Web search systems during which multiple information problems ordering, evolving information problems generating, searching task switching, task and mental coordinating occur, and at a deeper level, cognitive shifts take place. The explicit task level coordination is closely linked to multitasking behavior. The implicit cognitive level coordination is related to the task coordination process; this includes the evolution of information problem development and search task switching. Coordination mechanisms directly result in the shifts of cognitive states including strategy, evaluation, and view states which further affect users' holistic shifts in information problem understanding and knowledge contribution.

Based on the findings, a Web search model integrating multitasking, cognitive coordination and cognitive shifts (MCC model) is presented. Cognitive coordination as humans' vital capability under conscious control plays a nexus role in supporting multitasking Web searches and invoking the occurrence of shifts in cognition. The results extend multitasking research and Web search models in the field by examining and integrating underlying cognitive and coordination support mechanisms. Design recommendations for adaptive search systems are also put forward based on the characteristics and relationship of users' behaviors in multitasking, cognitive coordination and shifting.
Online consumer market inefficiencies and intermediation
Authors: Datta Pratim , Chatterjee Sutirtha
Published: June 2011

This paper seeks to empirically unravel why consumers sometimes need to trust intermediaries in online markets. Notwithstanding assertions that online markets will eventually eliminate the need for intermediaries, intermediaries remain an active part of the online market landscape. This paper tries to understand this phenomenon from a view of a consumer lack of trust in online markets and seeks to unearth what ultimately causes a lack of consumer trust in online markets and the role played by intermediaries in the mix. The paper proposes a model and empirically validates it. Findings suggest that inherent inefficiencies in online markets lead to consumer uncertainty. Perceptions of uncertainty lead to a lack of consumer trust in online markets. Consumer trust in online markets is restored only by placing trust in intermediaries.
Human clay models versus cat dissection: how the similarity between the classroom and the exam affects student performance
Authors: Waters John R. , Van Meter Peggy , Perrotti William , Drogo Salvatore , Cyr Richard J.
Published: June 2011

This study examined the effect of different anatomic representations on student learning in a human anatomy class studying the muscular system. Specifically, we examined the efficacy of using dissected cats (with and without handouts) compared with clay sculpting of human structures. Ten undergraduate laboratory sections were assigned to three treatment groups: cat dissection only, cat dissection with handouts, and human clay sculpting with handouts. Exams included higher-order questions that presented novel anatomic images and scenarios that the students did not practice in class. The higher-order anatomy exam questions varied the degree to which students in the different treatments had to transform the anatomic representation studied during laboratory activities to match the representation used in the exam questions. In this respect, exam questions manipulated the similarity between the surface features of the anatomic representations used in the classroom versus the exam. When identifying anatomic structures presented in a photograph or diagram, student performance improved significantly when transformation demands decreased, i.e., students in the human clay sculpting treatment group performed best on human anatomy questions and students in the cat dissection treatment group performed better on cat anatomy questions (independent of the use of handouts). There were similar, but nonsignificant, trends when students were asked functional anatomy questions presented in human and cat contexts. On survey questions designed to measure student attitudes about dissection versus nonanimal alternatives, students typically preferred the method used in their treatment group, suggesting that student preference is too fluid to factor into curricular decisions. When designing curricula, instructors must choose anatomic representations that support their course goals. Human representations are most effective when teaching the human muscular system.
Cross-disciplinary thermoregulation and sweat analysis laboratory experiences for undergraduate Chemistry and Exercise Science students
Authors: Mulligan Gregory , Taylor Nichole , Glen Mary , Tomlin Dona , Gaul Catherine A.
Published: June 2011

Cross-disciplinary (CD) learning experiences benefit student understanding of concepts and curriculum by offering opportunities to explore topics from the perspectives of alternate fields of study. This report involves a qualitative evaluation of CD health sciences undergraduate laboratory experiences in which concepts and students from two distinct disciplines [chemistry (CHEM) and exercise physiology (EPHE)] combined to study exercise thermoregulation and sweat analysis. Twenty-eight senior BSc Kinesiology (EPHE) students and 42 senior BSc CHEM students participated as part of their mutually exclusive, respective courses. The effectiveness of this laboratory environment was evaluated qualitatively using written comments collected from all students as well as from formal focus groups conducted after the CD laboratory with a representative cohort from each class ( n = 16 CHEM students and 9 EPHE students). An open coding strategy was used to analyze the data from written feedback and focus group transcripts. Coding topics were generated and used to develop five themes found to be consistent for both groups of students. These themes reflected the common student perceptions that the CD experience was valuable and that students enjoyed being able to apply academic concepts to practical situations as well as the opportunity to interact with students from another discipline of study. However, students also reported some challenges throughout this experience that stemmed from the combination of laboratory groups from different disciplines with limited modification to the design of the original, pre-CD, learning environments. The results indicate that this laboratory created an effective learning opportunity that fostered student interest and enthusiasm for learning. The findings also provide information that could inform subsequent design and implementation of similar CD experiences to enhance engagement of all students and improve instructor efficacy.
The zebrafish brain in research and teaching: a simple in vivo and in vitro model for the study of spontaneous neural activity
Authors: Vargas R. , Jóhannesdóttir I. þ. , Sigurgeirsson B. , þorsteinsson H. , Karlsson K. Æ.
Published: June 2011

Recently, the zebrafish ( Danio rerio ) has been established as a key animal model in neuroscience. Behavioral, genetic, and immunohistochemical techniques have been used to describe the connectivity of diverse neural circuits. However, few studies have used zebrafish to understand the function of cerebral structures or to study neural circuits. Information about the techniques used to obtain a workable preparation is not readily available. Here, we describe a complete protocol for obtaining in vitro and in vivo zebrafish brain preparations. In addition, we performed extracellular recordings in the whole brain, brain slices, and immobilized nonanesthetized larval zebrafish to evaluate the viability of the tissue. Each type of preparation can be used to detect spontaneous activity, to determine patterns of activity in specific brain areas with unknown functions, or to assess the functional roles of different neuronal groups during brain development in zebrafish. The technique described offers a guide that will provide innovative and broad opportunities to beginner students and researchers who are interested in the functional analysis of neuronal activity, plasticity, and neural development in the zebrafish brain.
Molecular motors: how to make models that can be used to convey the concept of molecular ratchets and thermal capture
Authors: DoHarris Lindsay , Giesler Amanda , Humber Brent , Sukumar Aravin , Janssen Luke J.
Published: June 2011

A wide variety of cellular processes use molecular motors, including processive motors that move along some form of track (e.g ., myosin with actin, kinesin or dynein with tubulin) and polymerases that move along a template (e.g. , DNA and RNA polymerases, ribosomes). In trying to understand how these molecular motors actually move, many apply their understanding of how man-made motors work: the latter use some form of energy to exert a force or torque on its load. However, quite a different mechanism has been proposed to possibly account for the movement of molecular motors. Rather than hydrolyzing ATP to push or pull their load, they might use their own thermal vibrational energy as well as that of their load and their environment to move the load, capturing those movements that occur along a desired vector or axis and resisting others; ATP hydrolysis is required to make backward movements impossible. This intriguing thermal capture or Brownian ratchet model is relatively more difficult to convey to students. In this report, we describe several teaching aids that are very easily constructed using widely available household materials to convey the concept of a molecular ratchet.
Inhalation of hydrogen gas attenuates left ventricular remodeling induced by intermittent hypoxia in mice
Authors: Hayashi Tetsuya , Yoshioka Toshitaka , Hasegawa Kenichi , Miyamura Masatoshi , Mori Tatsuhiko , Ukimura Akira , Matsumura Yasuo , Ishizaka Nobukazu
Published: June 2011

Sleep apnea syndrome increases the risk of cardiovascular morbidity and mortality. We previously reported that intermittent hypoxia increases superoxide production in a manner dependent on nicotinamide adenine dinucleotide phosphate and accelerates adverse left ventricular (LV) remodeling. Recent studies have suggested that hydrogen (H2) may have an antioxidant effect by reducing hydroxyl radicals. In this study, we investigated the effects of H2gas inhalation on lipid metabolism and LV remodeling induced by intermittent hypoxia in mice. Male C57BL/6J mice ( n = 62) were exposed to intermittent hypoxia (repetitive cycle of 1-min periods of 5 and 21% oxygen for 8 h during daytime) for 7 days. H2gas (1.3 vol/100 vol) was given either at the time of reoxygenation, during hypoxic conditions, or throughout the experimental period. Mice kept under normoxic conditions served as controls ( n = 13). Intermittent hypoxia significantly increased plasma levels of low- and very low-density cholesterol and the amount of 4-hydroxy-2-nonenal-modified protein adducts in the LV myocardium. It also upregulated mRNA expression of tissue necrosis factor-α, interleukin-6, and brain natriuretic peptide, increased production of superoxide, and induced cardiomyocyte hypertrophy, nuclear deformity, mitochondrial degeneration, and interstitial fibrosis. H2gas inhalation significantly suppressed these changes induced by intermittent hypoxia. In particular, H2gas inhaled at the timing of reoxygenation or throughout the experiment was effective in preventing dyslipidemia and suppressing superoxide production in the LV myocardium. These results suggest that inhalation of H2gas was effective for reducing oxidative stress and preventing LV remodeling induced by intermittent hypoxia relevant to sleep apnea.
Cutaneous constitutive nitric oxide synthase activation in postural tachycardia syndrome with splanchnic hyperemia
Authors: Stewart Julian M. , Nafday Abhinav , Ocon Anthony J. , Terilli Courtney , Medow Marvin S.
Published: June 2011

Models of microgravity are linked to excessive constitutive nitric oxide (NO) synthase (NOS), splanchnic vasodilation, and orthostatic intolerance. Normal-flow postural tachycardia syndrome (POTS) is a form of chronic orthostatic intolerance associated with splanchnic hyperemia. To test the hypothesis that there is excessive constitutive NOS in POTS, we determined whether cutaneous microvascular neuronal NO and endothelial NO are increased. We performed two sets of experiments in POTS and control subjects aged 21.4 ± 2 yr. We used laser-Doppler flowmetry to measure the cutaneous response to local heating as an indicator of bioavailable neuronal NO. To test for bioavailable endothelial NO, we infused intradermal acetylcholine through intradermal microdialysis catheters and used the selective neuronal NOS inhibitor l- Nω-nitroarginine-2,4-l-diamino-butyric amide (Nω, 10 mM), the selective inducible NOS inhibitor aminoguanidine (10 mM), the nonspecific NOS inhibitor nitro-l-arginine (NLA, 10 mM), or Ringer solution. The acetylcholine dose response and the NO-dependent plateau of the local heating response were increased in POTS compared with those in control subjects. The local heating plateau was significantly higher, 98 ± 1%maximum cutaneous vascular conductance (%CVCmax) in POTS compared with 88 ± 2%CVCmax in control subjects but decreased to the same level with Nω (46 ± 5%CVCmax in POTS compared with 49 ± 4%CVCmax in control) or with NLA (45 ± 3%CVCmax in POTS compared with 47 ± 4%CVCmax in control). Only NLA blunted the acetylcholine dose response, indicating that NO produced by endothelial NOS was released by acetylcholine. Aminoguanidine was without effect. This is consistent with increased endothelial and neuronal NOS activity in normal-flow POTS.
Heterogenous vasodilator pathways underlie flow-mediated dilation in men and women
Authors: Parker Beth A. , Tschakovsky Michael E. , Augeri Amanda L. , Polk Donna M. , Thompson Paul D. , Kiernan Francis J.
Published: June 2011

This study investigated the sex differences in the contribution of nitric oxide (NO) and prostaglandins (PGs) to flow-mediated dilation (FMD). Radial artery (RA) FMD, assessed as the dilatory response to 5-min distal cuff occlusion, was repeated after three separate brachial artery infusions of saline (SAL), NG-monomethyl-l-arginine (l-NMMA), and ketorolac (KETO) + l-NMMA in healthy younger men (M; n = 8) and women (W; n = 8). In eight subjects (4 M, 4W) RA FMD was reassessed on a separate day with drug order reversed (SAL, KETO, and l-NMMA + KETO). RA FMD was calculated as the peak dilatory response observed relative to baseline (%FMD) and expressed relative to the corresponding area under the curve shear stress (%FMD/AUC SS). l-NMMA reduced %FMD similarly and modestly ( P = 0.68 for sex * trial interaction) in M and W (all subjects: 10.0 ± 3.8 to 7.6 ± 4.7%; P = 0.03) with no further effect of KETO ( P = 0.68). However, all sex * trial and trial effects on %FMD/AUC SS for l-NMMA and KETO + l-NMMA were insignificant (all P > 0.20). There was also substantial heterogeneity of the magnitude and direction of dilator responses to blockade. After l-NMMA infusion, subjects exhibited both reduced ( n = 14; range: 11 to 78% decrease) and augmented ( n = 2; range: 1 to 96% increase) %FMD. Following KETO + l-NMMA, seven subjects exhibited reduced dilation (range: 10 to 115% decrease) and nine subjects exhibited augmented dilation (range: 1 to 212% increase). Reversing drug order did not change the nature of the findings. These findings suggest that RA FMD is not fully or uniformly NO dependent in either men or women, and that there is heterogeneity in the pathways underlying the conduit dilatory response to ischemia.
Liver growth factor treatment restores cell-extracellular matrix balance in resistance arteries and improves left ventricular hypertrophy in SHR
Authors: Conde M. Victoria , Gonzalez M. Carmen , Quintana-Villamandos Begoña , Abderrahim Fatima , Briones Ana M. , Condezo-Hoyos Luis , Regadera Javier , Susin Cristina , Gomez de Diego Jose J. , Delgado-Baeza Emilio , Diaz-Gil Juan J. , Arribas Silvia M.
Published: June 2011

Liver growth factor (LGF) is an endogenous albumin-bilirubin complex with antihypertensive effects in spontaneously hypertensive rats (SHR). We assessed the actions of LGF treatment on SHR mesenteric resistance and intramyocardial arteries (MRA and IMA, respectively), heart, and vascular smooth muscle cells (VSMC). SHR and Wistar-Kyoto (WKY) rats treated with vehicle or LGF (4.5 μg LGF/rat, 4 ip injections over 12 days) were used. Intra-arterial blood pressure was measured in anesthetized rats. The heart was weighted and paraffin-embedded. Proliferation, ploidy, and fibronectin deposition were studied in carotid artery-derived VSMC by immunocytochemistry. In MRA, we assessed: 1) geometry and mechanics by pressure myography; 2) function by wire myography; 3) collagen by sirius red staining and polarized light microscopy, and 4) elastin, cell density, nitric oxide (NO), and superoxide anion by confocal microscopy. Heart sections were used to assess cell density and collagen content in IMA. Left ventricular hypertrophy (LVH) regression was assessed by echocardiography. LGF reduced blood pressure only in SHR. LGF in vitro or as treatment normalized the alterations in proliferation and fibronectin in SHR-derived VSMC with no effect on WKY cells. In MRA, LGF treatment normalized collagen, elastin, and VSMC content and passive mechanical properties. In addition, it improved NO availability through reduction of superoxide anion. In IMA, LGF treatment normalized perivascular collagen and VSMC density, improving the wall-to-lumen ratio. Paired experiments demonstrated a partial regression of SHR LVH by LGF treatment. The effective cardiovascular antifibrotic and regenerative actions of LGF support its potential in the treatment of hypertension and its complications.
Glucan phosphate attenuates myocardial HMGB1 translocation in severe sepsis through inhibiting NF-κB activation
Authors: Ha Tuanzhu , Xia Yeling , Liu Xiang , Lu Chen , Liu Li , Kelley Jim , Kalbfleisch John , Kao Race L. , Williams David L. , Li Chuanfu
Published: June 2011

Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. High-mobility group box 1 (HMGB1) serves as a late mediator of lethality in sepsis. We have reported that glucan phosphate (GP) attenuates cardiac dysfunction and increases survival in cecal ligation and puncture (CLP)-induced septic mice. In the present study, we examined the effect of GP on HMGB1 translocation from the nucleus to the cytoplasm in the myocardium of septic mice. GP was administered to mice 1 h before induction of CLP. Sham-operated mice served as control. The levels of HMGB1, Toll-like receptor 4 (TLR4), and NF-κB binding activity were examined. In an in vitro study, H9C2 cardiomyoblasts were treated with lipopolysaccharide (LPS) in the presence or absence of GP. H9C2 cells were also transfected with Ad5-IκBα mutant, a super repressor of NF-κB activity, before LPS stimulation. CLP significantly increased the levels of HMGB1, TLR4, and NF-κB binding activity in the myocardium. In contrast, GP administration attenuated CLP-induced HMGB1 translocation from the nucleus to the cytoplasm and reduced CLP-induced increases in TLR4 and NF-κB activity in the myocardium. In vitro studies showed that GP prevented LPS-induced HMGB1 translocation and NF-κB binding activity. Blocking NF-κB binding activity by Ad5-IκBα attenuated LPS-induced HMGB1 translocation. GP administration also reduced the LPS-stimulated interaction of HMGB1 with TLR4. These data suggest that attenuation of HMGB1 translocation by GP is mediated through inhibition of NF-κB activation in CLP-induced sepsis and that activation of NF-κB is required for HMGB1 translocation.
Increased folding and channel activity of a rare cystic fibrosis mutant with CFTR modulators
Authors: Caldwell Ray A. , Grove Diane E. , Houck Scott A. , Cyr Douglas M.
Published: June 2011

Cystic fibrosis (CF) is a lethal recessive genetic disease caused by mutations in the CFTR gene. The gene product is a PKA-regulated anion channel that is important for fluid and electrolyte transport in the epithelia of lung, gut, and ducts of the pancreas and sweat glands. The most common CFTR mutation, ΔF508, causes a severe, but correctable, folding defect and gating abnormality, resulting in negligible CFTR function and disease. There are also a large number of rare CF-related mutations where disease is caused by CFTR misfolding. Yet the extent to which defective biogenesis of these CFTR mutants can be corrected is not clear. CFTRV232D is one such mutant that exhibits defective folding and trafficking. CFTRΔF508 misfolding is difficult to correct, but defective biogenesis of CFTRV232D is corrected to near wild-type levels by small-molecule folding correctors in development as CF therapeutics. To determine if CFTRV232D protein is competent as a Cl− channel, we utilized single-channel recordings from transfected human embryonic kidney (HEK-293) cells. After PKA stimulation, CFTRV232D channels were detected in patches with a unitary Cl− conductance indistinguishable from that of CFTR. Yet the frequency of detecting CFTRV232D channels was reduced to ∼20% of patches compared with 60% for CFTR. The folding corrector Corr-4a increased the CFTRV232D channel detection rate and activity to levels similar to CFTR. CFTRV232D-corrected channels were inhibited with CFTRinh-172 and stimulated fourfold by the CFTR channel potentiator VRT-532. These data suggest that CF patients with rare mutations that cause CFTR misfolding, such as CFTRV232D, may benefit from treatment with folding correctors and channel potentiators in development to restore CFTRΔF508 function.
Lower vascular tone and larger plasma volume in Parkinson's disease with orthostatic hypotension
Authors: Groothuis J. T. , Esselink R. A. J. , Seeger J. P. H. , van Aalst M. J. H. , Hopman M. T. E. , Bloem B. R.
Published: June 2011

The pathophysiology of orthostatic hypotension in Parkinson's disease (PD) is incompletely understood. The primary focus has thus far been on failure of the baroreflex, a central mediated vasoconstrictor mechanism. Here, we test the role of two other possible factors: 1) a reduced peripheral vasoconstriction (which may contribute because PD includes a generalized sympathetic denervation); and 2) an inadequate plasma volume (which may explain why plasma volume expansion can manage orthostatic hypotension in PD). We included 11 PD patients with orthostatic hypotension (PD + OH), 14 PD patients without orthostatic hypotension (PD − OH), and 15 age-matched healthy controls. Leg blood flow was examined using duplex ultrasound during 60° head-up tilt. Leg vascular resistance was calculated as the arterial-venous pressure gradient divided by blood flow. In a subset of 9 PD + OH, 9 PD − OH, and 8 controls, plasma volume was determined by indicator dilution method with radiolabeled albumin (125I-HSA). The basal leg vascular resistance was significantly lower in PD + OH (0.7 ± 0.3 mmHg·ml−1·min) compared with PD − OH (1.3 ± 0.6 mmHg·ml−1·min, P < 0.01) and controls (1.3 ± 0.5 mmHg·ml−1·min, P < 0.01). Leg vascular resistance increased significantly during 60° head-up tilt with no significant difference between the groups. Plasma volume was significantly larger in PD + OH (3,869 ± 265 ml) compared with PD − OH (3,123 ± 377 ml, P < 0.01) and controls (3,204 ± 537 ml, P < 0.01). These results indicate that PD + OH have a lower basal leg vascular resistance in combination with a larger plasma volume compared with PD − OH and controls. Despite the increase in leg vascular resistance during 60° head-up tilt, PD + OH are unable to maintain their blood pressure.
Time course of isotonic shortening and the underlying contraction mechanism in airway smooth muscle
Authors: Syyong Harley T. , Raqeeb Abdul , Paré Peter D. , Seow Chun Y.
Published: June 2011

Although the structure of the contractile unit in smooth muscle is poorly understood, some of the mechanical properties of the muscle suggest that a sliding-filament mechanism, similar to that in striated muscle, is also operative in smooth muscle. To test the applicability of this mechanism to smooth muscle function, we have constructed a mathematical model based on a hypothetical structure of the smooth muscle contractile unit: a side-polar myosin filament sandwiched by actin filaments, each attached to the equivalent of a Z disk. Model prediction of isotonic shortening as a function of time was compared with data from experiments using ovine tracheal smooth muscle. After equilibration and establishment of in situ length, the muscle was stimulated with ACh (100 μM) until force reached a plateau. The muscle was then allowed to shorten isotonically against various loads. From the experimental records, length-force and force-velocity relationships were obtained. Integration of the hyperbolic force-velocity relationship and the linear length-force relationship yielded an exponential function that approximated the time course of isotonic shortening generated by the modeled sliding-filament mechanism. However, to obtain an accurate fit, it was necessary to incorporate a viscoelastic element in series with the sliding-filament mechanism. The results suggest that a large portion of the shortening is due to filament sliding associated with muscle activation and that a small portion is due to continued deformation associated with an element that shows viscoelastic or power-law creep after a step change in force.
Effects of simulated reflux laryngitis on laryngeal chemoreflexes in newborn lambs
Authors: Carreau Anne-Marie , Patural Hugues , Samson Nathalie , Doueik Alexandre A. , Hamon Julie , Fortier Pierre-Hugues , Praud Jean-Paul
Published: June 2011

It has been suggested that reflux laryngitis (RL) is involved in apneas-bradycardias of the newborn. The aim of the present study was to develop a unique RL model in newborn lambs to test the hypothesis that RL enhances the cardiorespiratory components of the laryngeal chemoreflexes (LCR) in the neonatal period. Gastric juice surrogate (2 ml of normal saline solution with HCl pH 2 + pepsin 300 U/ml) (RL group, n = 6) or normal saline (control group, n = 6) was repeatedly injected onto the posterior aspect of the larynx, 3 times a day for 6 consecutive days, via a retrograde catheter introduced into the cervical esophagus. Lambs instilled with gastric juice surrogate presented clinical signs of RL, as well as moderate laryngitis on histological observation. Laryngeal chemoreflexes were thereafter induced during sleep by injection of 0.5 ml of HCl (pH 2), ewe's milk, distilled water or saline into the laryngeal vestibule via a chronic, transcutaneous supraglottal catheter. Overall, RL led to a significantly greater respiratory inhibition compared with the control group during LCR, including longer apnea duration ( P = 0.01), lower minimal respiratory rate ( P = 0.002), and a more prominent decrease in arterial hemoglobin saturation (SpO2) ( P = 0.03). No effects were observed on cardiac variables. In conclusion, 1) our unique neonatal ovine model presents clinical and histological characteristics of RL; and 2) the presence of RL in newborn lambs increases the respiratory inhibition observed with LCR, at times leading to severe apneas and desaturations.
Giant sucking sound: can physiology fill the intellectual void left by the reductionists?
Authors: Joyner Michael J.
Published: June 2011

Molecular reductionism has so far failed to deliver the broad-based therapeutic insights that were initially hoped for. This form of reductionism is now being replaced by so-called “systems biology.” This is a nebulously defined approach and/or discipline, with some versions of it relying excessively on hypothesis-neutral approaches and only minimally informed by key physiological concepts such as homeostasis and regulation. In this context, physiology is uniquely positioned to continue to provide impressive levels of both biological and therapeutic insight by using hypothesis-driven “classical” approaches and concepts to help frame what might be described as the “pieces of the puzzle” that emerge from molecular reductionism. The strength of physiology as a “bridge” between reductionism and epidemiology, along with its unparalleled ability to generate therapeutic insights and opportunities justifies increased attention and emphasis on our discipline into the future. Arguments relevant to this set of assertions are advanced and this paper, which was based on the 2011 Adolph Lecture, represents an effort to fill the intellectual void left by reductionism and improve scientific progress.
Increased palmitoyl-myristoyl-phosphatidylcholine in neonatal rat surfactant is lung specific and correlates with oral myristic acid supply
Authors: Bernhard Wolfgang , Raith Marco , Pynn Christopher J. , Gille Christian , Stichtenoth Guido , Stoll Dieter , Schleicher Erwin , Poets Christian F.
Published: June 2011

Surfactant predominantly comprises phosphatidylcholine (PC) species, together with phosphatidylglycerols, phosphatidylinositols, neutral lipids, and surfactant proteins-A to -D. Together, dipalmitoyl-PC (PC16:0/16:0), palmitoyl-myristoyl-PC (PC16:0/14:0), and palmitoyl-palmitoleoyl-PC (PC16:0/16:1) make up 75–80% of mammalian surfactant PC, the proportions of which vary during development and in chronic lung diseases. PC16:0/14:0, which exerts specific effects on macrophage differentiation in vitro, increases in surfactant during alveolarization (at the expense of PC16:0/16:0), a prenatal event in humans but postnatal in rats. The mechanisms responsible and the significance of this reversible increase are, however, not understood. We hypothesized that, in rats, myristic acid (C14:0) enriched milk is key to lung-specific PC16:0/14:0 increases in surfactant. We found that surfactant PC16:0/14:0 in suckling rats correlates with C14:0 concentration in plasma chylomicrons and lung tissue triglycerides, and that PC16:0/14:0 fractions reflect exogenous C14:0 supply. Significantly, C14:0 was increased neither in plasma PC, nor in liver triglycerides, free fatty acids, or PC. Lauric acid was also abundant in triglycerides, but was not incorporated into surfactant PC. Comparing a C14:0-rich milk diet with a C14:0-poor carbohydrate diet revealed increased C14:0 and decreased C16:0 in plasma and lung triglycerides, respectively. PC16:0/14:0 enrichment at the expense of PC16:0/16:0 did not impair surfactant surface tension function. However, the PC profile of the alveolar macrophages from the milk-fed animals changed from PC16:0/16:0 rich to PC16:0/14:0 rich. This was accompanied by reduced reactive oxygen species production. We propose that nutritional supply with C14:0 and its lung-specific enrichment may contribute to decreased reactive oxygen species production during alveolarization.
Mechanisms of increase in cardiac output during acute weightlessness in humans
Authors: Petersen Lonnie G. , Damgaard Morten , Petersen Johan C. G. , Norsk Peter
Published: June 2011

Based on previous water immersion results, we tested the hypothesis that the acute 0-G-induced increase in cardiac output (CO) is primarily caused by redistribution of blood from the vasculature above the legs to the cardiopulmonary circulation. In seated subjects ( n = 8), 20 s of 0 G induced by parabolic flight increased CO by 1.7 ± 0.4 l/min ( P < 0.001). This increase was diminished to 0.8 ± 0.4 l/min ( P = 0.028), when venous return from the legs was prevented by bilateral venous thigh-cuff inflation (CI) of 60 mmHg. Because the increase in stroke volume during 0 G was unaffected by CI, the lesser increase in CO during 0 G + CI was entirely caused by a lower heart rate (HR). Thus blood from vascular beds above the legs in seated subjects can alone account for some 50% of the increase in CO during acute 0 G. The remaining increase in CO is caused by a higher HR, of which the origin of blood is unresolved. In supine subjects, CO increased from 7.1 ± 0.7 to 7.9 ± 0.8 l/min ( P = 0.037) when entering 0 G, which was solely caused by an increase in HR, because stroke volume was unaffected. In conclusion, blood originating from vascular beds above the legs can alone account for one-half of the increase in CO during acute 0 G in seated humans. A Bainbridge-like reflex could be the mechanism for the HR-induced increase in CO during 0 G in particular in supine subjects.
Histamine Blood Concentration in Ischemic Heart Disease Patients
Authors: Zdravkovic Vladimir , Pantovic Suzana , Rosic Gvozden , Tomic-Lucic Aleksandra , Zdravkovic Nemanja , Colic Maja , Obradovic Zdravko , Rosic Mirko
Published: June 2011

The aim of this study was to investigate histamine blood concentration in subjects suffering from different types of ischemic heart diseases during the period of eight days. Our results showed that the histamine blood level was associated with different types of ischemic heart diseases. The blood histamine level in all investigated patients was significantly higher when compared to control subjects (44.87 ± 1.09 ng mL−1), indicating the increase of histamine release in patients suffering from coronary diseases. In patients suffering from ACS‐UA and ACS‐STEMI, the second day peak of histamine level occurs (90.85 ± 6.34 ng mL−1 and 121.7 ± 6.34 ng mL−1, resp.) probably as the reperfusion event. Furthermore, our data suggest that histamine can be additional parameter of myocardial ischemia along with cardiac specific enzymes and may prove to be an excellent single prognostic marker for multitude of ischemic heart diseases.
Combined Gene Expression Profiling and RNAi Screening in Clear Cell Renal Cell Carcinoma Identify PLK1 and Other Therapeutic Kinase Targets
Authors: Ding Yan , Huang Dan , Zhang Zhongfa , Smith Josh , Petillo David , Looyenga Brendan D. , Feenstra Kristin , MacKeigan Jeffrey P. , Furge Kyle A. , Teh Bin T.
Published: June 2011

In recent years, several molecularly targeted therapies have been approved for clear cell renal cell carcinoma (ccRCC), a highly aggressive cancer. Although these therapies significantly extend overall survival, nearly all patients with advanced ccRCC eventually succumb to the disease. To identify other molecular targets, we profiled gene expression in 90 ccRCC patient specimens for which tumor grade information was available. Gene set enrichment analysis indicated that cell-cycle–related genes, in particular, Polo-like kinase 1 (PLK1), were associated with disease aggressiveness. We also carried out RNAi screening to identify kinases and phosphatases that when inhibited could prevent cell proliferation. As expected, RNAi-mediated knockdown of PLK1 and other cell-cycle kinases was sufficient to suppress ccRCC cell proliferation. The association of PLK1 in both disease aggression and in vitro growth prompted us to examine the effects of a small-molecule inhibitor of PLK1, BI 2536, in ccRCC cell lines. BI 2536 inhibited the proliferation of ccRCC cell lines at concentrations required to inhibit PLK1 kinase activity, and sustained inhibition of PLK1 by BI 2536 led to dramatic regression of ccRCC xenograft tumors in vivo. Taken together, these findings highlight PLK1 as a rational therapeutic target for ccRCC. Cancer Res; 71(15); 5225–34. ©2011 AACR.
Two Novel Determinants of Etoposide Resistance in Small Cell Lung Cancer
Authors: Lawson Malcolm H. , Cummings Natalie M. , Rassl Doris M. , Russell Roslin , Brenton James D. , Rintoul Robert C. , Murphy Gillian
Published: June 2011

Patient survival in small cell lung cancer (SCLC) is limited by acquired chemoresistance. Here we report the use of a biologically relevant model to identify novel candidate genes mediating in vivo acquired resistance to etoposide. Candidate genes derived from a cDNA microarray analysis were cloned and transiently overexpressed to evaluate their potential functional roles. We identified two promising genes in the DNA repair enzyme DNA polymerase β and in the neuroendocrine transcription factor NKX2.2. Specific inhibition of DNA polymerase β reduced the numbers of cells surviving treatment with etoposide and increased the amount of DNA damage in cells. Conversely, stable overexpression of NKX2.2 increased cell survival in response to etoposide in SCLC cell lines. Consistent with these findings, we found that an absence of nuclear staining for NKX2.2 in SCLC primary tumors was an independent predictor of improved outcomes in chemotherapy-treated patients. Taken together, our findings justify future prospective studies to confirm the roles of these molecules in mediating chemotherapy resistance in SCLC. Cancer Res; 71(14); 4877–87. ©2011 AACR.
Mechanical Stiffness Grades Metastatic Potential in Patient Tumor Cells and in Cancer Cell Lines
Authors: Swaminathan Vinay , Mythreye Karthikeyan , O'Brien E. Tim , Berchuck Andrew , Blobe Gerard C. , Superfine Richard
Published: June 2011

Cancer cells are defined by their ability to invade through the basement membrane, a critical step during metastasis. While increased secretion of proteases, which facilitates degradation of the basement membrane, and alterations in the cytoskeletal architecture of cancer cells have been previously studied, the contribution of the mechanical properties of cells in invasion is unclear. Here, we applied a magnetic tweezer system to establish that stiffness of patient tumor cells and cancer cell lines inversely correlates with migration and invasion through three-dimensional basement membranes, a correlation known as a power law. We found that cancer cells with the highest migratory and invasive potential are five times less stiff than cells with the lowest migration and invasion potential. Moreover, decreasing cell stiffness by pharmacologic inhibition of myosin II increases invasiveness, whereas increasing cell stiffness by restoring expression of the metastasis suppressor TβRIII/betaglycan decreases invasiveness. These findings are the first demonstration of the power-law relation between the stiffness and the invasiveness of cancer cells and show that mechanical phenotypes can be used to grade the metastatic potential of cell populations with the potential for single cell grading. The measurement of a mechanical phenotype, taking minutes rather than hours needed for invasion assays, is promising as a quantitative diagnostic method and as a discovery tool for therapeutics. By showing that altering stiffness predictably alters invasiveness, our results indicate that pathways regulating these mechanical phenotypes are novel targets for molecular therapy of cancer. Cancer Res; 71(15); 5075–80. ©2011 AACR.
The Efficacy of IGF-I Receptor Monoclonal Antibody against Human Gastrointestinal Carcinomas is Independent of k-ras Mutation Status
Authors: Ii Masanori , Li Hua , Adachi Yasushi , Yamamoto Hiroyuki , Ohashi Hirokazu , Taniguchi Hiroaki , Arimura Yoshiaki , Carbone David P. , Imai Kohzoh , Shinomura Yasuhisa
Published: June 2011

Purpose: Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal cancers. We have previously shown successful targeting therapy for colorectal, pancreatic, gastric, and esophageal carcinomas using recombinant adenoviruses expressing dominant negative IGF-IR. Mutation in k-ras is one of key factors in gastrointestinal cancers. In this study, we sought to evaluate the effect of a new monoclonal antibody for IGF-IR, figitumumab (CP-751,871), on the progression of human gastrointestinal carcinomas with/without k-ras mutation.

Experimental Design: We assessed the effect of figitumumab on signal transduction, proliferation, and survival in six gastrointestinal cancer cell lines with/without k-ras mutation, including colorectal and pancreatic adenocarcinoma, esophageal squamous cell carcinoma, and hepatoma. Combination effects of figitumumab and chemotherapy were also studied. Then figitumumab was evaluated in the treatment of xenografts in nude mice.

Results: Figitumumab blocked autophosphorylation of IGF-IR and its downstream signals. The antibody suppressed proliferation and tumorigenicity in all cell lines. Figitumumab inhibited survival by itself and up-regulated chemotherapy (5-FU and gemcitabine) induced apoptosis. Moreover, the combination of this agent and chemotherapy was effective against tumors in mice. The effect of figitumumab was not influenced by the mutation status of k-ras. Figitumumab reduced expression of IGF-IR but not insulin receptor in these xenografted tumors. The drug did not affect murine body weight or blood concentrations of glucose, insulin, IGF binding protein 3, and growth hormone.

Conclusions: IGF-IR might be a good molecular therapeutic target and figitumumab may thus have therapeutic value in human gastrointestinal malignancies even in the presence of k-ras mutations. Clin Cancer Res; 17(15); 5048–59. ©2011 AACR.