bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetics and the Language Sciences
Authors: Fisher Simon E. , Vernes Sonja C.
Published: August 2014

Theories addressing the biological basis of language must be built on an appreciation of the ways that molecular and neurobiological substrates can contribute to aspects of human cognition. Here, we lay out the principles by which a genome could potentially encode the necessary information to produce a language-ready brain. We describe what genes are; how they are regulated; and how they affect the formation, function, and plasticity of neuronal circuits. At each step, we give examples of molecules implicated in pathways that are important for speech and language. Finally, we discuss technological advances in genomics that are revealing considerable genotypic variation in the human population, from rare mutations to common polymorphisms, with the potential to relate this variation to natural variability in speech and language skills. Moving forward, an interdisciplinary approach to the language sciences, integrating genetics, neurobiology, psychology, and linguistics, will be essential for a complete understanding of our unique human capacities.
The Dynamics of Greenland's Glacial Fjords and Their Role in Climate
Authors: Straneo Fiamma , Cenedese Claudia
Published: August 2014

Rapid mass loss from the Greenland Ice Sheet has sparked interest in its glacial fjords for two main reasons: Increased submarine melting of glaciers terminating in fjords is a plausible trigger for glacier retreat, and the anomalous freshwater discharged from Greenland is transformed by fjord processes before being released into the large-scale ocean. Knowledge of the fjords' dynamics is thus key to understanding ice sheet variability and its impact on climate. Although Greenland's fjords share some commonalities with other fjords, their deep sills and deeply grounded glaciers, the presence of Atlantic and Polar Waters on the continental shelves outside the fjords' mouths, and the seasonal discharge at depth of large amounts of surface melt make them unique systems that do not fit existing paradigms. Major gaps in understanding include the interaction of the buoyancy-driven circulation (forced by the glacier) and shelf-driven circulation, and the dynamics in the near-ice zone. These must be addressed before appropriate forcing conditions can be supplied to ice sheet and ocean/climate models.
Phytoplankton Strategies for Photosynthetic Energy Allocation
Authors: Halsey Kimberly H. , Jones Bethan M.
Published: August 2014

Phytoplankton physiology is dynamic and highly responsive to the environment. Phytoplankton acclimate to changing environmental conditions by a complex reallocation of carbon and energy through metabolic pathways to optimize growth. Considering the tremendous diversity of phytoplankton, it is not surprising that different phytoplankton taxa use different strategies to partition carbon and energy resources. It has therefore been satisfying to discover that general principles of energetic stoichiometry appear to govern these complex processes and can be broadly applied to interpret phytoplankton distributions, productivity, and food web dynamics. The expectation of future changes in aquatic environments brought on by climate change warrants gathering knowledge about underlying patterns of photosynthetic energy allocation and their impacts on community structure and ecosystem productivity.
Brown, Beige, and White: The New Color Code of Fat and Its Pharmacological Implications
Authors: Pfeifer Alexander , Hoffmann Linda S.
Published: August 2014

Brown adipose tissue (BAT) was previously regarded as a special type of fat relevant only for defending hibernating animals and newborns against a cold environment. Recently, BAT has received considerable attention following its (re)discovery in humans. Using glucose tracers, multiple laboratories independently found metabolically active BAT in adults. The enormous metabolic powers of BAT in animal models could make it an attractive target for antiobesity therapies in humans. Here, we review the present knowledge on the role of BAT in energy homeostasis and metabolism, focusing on signaling pathways and potential targets for novel therapeutics. We also shine light on ongoing debates, including those about the true color of brown fat in adults, as well as on the requirements for translation of basic research on BAT into clinical medicine.
The Design of Covalent Allosteric Drugs
Authors: Nussinov Ruth , Tsai Chung-Jung
Published: August 2014

A key issue in drug discovery is how to reduce drug dosage and increase specificity while retaining or increasing efficacy, as high dosage is often linked to toxicity. There are two types of drugs on the market: orthosteric and allosteric. Orthosteric drugs can be noncovalent or covalent. The latter are advantageous because they may be prescribed in lower doses, but their potential off-target toxicity is a primary concern. The chief advantages of allosteric drugs are their higher specificity and their consequently lower chance of toxic side effects. Covalent allosteric drugs combine the pharmacological merits of covalent drugs with the additional benefit of the higher specificity of allosteric drugs. In a recent promising step in therapeutic drug development, allosteric, disulfide-tethered fragments successfully modulated the activity of a protein kinase and K-Ras.
How Good Is “Evidence” from Clinical Studies of Drug Effects and Why Might Such Evidence Fail in the Prediction of the Clinical Utility of Drugs?
Authors: Naci Huseyin , Ioannidis John P.A.
Published: August 2014

Promising evidence from clinical studies of drug effects does not always translate to improvements in patient outcomes. In this review, we discuss why early evidence is often ill suited to the task of predicting the clinical utility of drugs. The current gap between initially described drug effects and their subsequent clinical utility results from deficits in the design, conduct, analysis, reporting, and synthesis of clinical studies—often creating conditions that generate favorable, but ultimately incorrect, conclusions regarding drug effects. There are potential solutions that could improve the relevance of clinical evidence in predicting the real-world effectiveness of drugs. What is needed is a new emphasis on clinical utility, with nonconflicted entities playing a greater role in the generation, synthesis, and interpretation of clinical evidence. Clinical studies should adopt strong design features, reflect clinical practice, and evaluate outcomes and comparisons that are meaningful to patients. Transformative changes to the research agenda may generate more meaningful and accurate evidence on drug effects to guide clinical decision making.
The Ethics and Economics of Pharmaceutical Pricing
Authors: Parker-Lue Sara , Santoro Michael , Koski Greg
Published: August 2014

The cost of drugs is a major and rapidly rising component of health-care expenditures. We survey recent literature on the ethics and economics of skyrocketing pharmaceutical prices and find that advances in economic research have increased the sharpness and focus of the ethically based calls to increase access by modifying patent protection and reducing prices. In some cases, research supports ethical arguments for broader access. Other research suggests that efforts to broaden access result in unintended consequences for innovation and the medical needs of patients. Both ethicists and economists need to be more cognizant of the real clinical settings in which physicians practice medicine with real patients. Greater cross-disciplinary interaction among economists, ethicists, and physicians can help reduce the disjunction between innovation and access and improve access and patient care. This dialogue will impact private industry and may spur new multistakeholder paradigms for drug discovery, development, and pricing.
Dynamics of Lung Defense in Pneumonia: Resistance, Resilience, and Remodeling
Authors: Quinton Lee J. , Mizgerd Joseph P.
Published: August 2014

Pneumonia is initiated by microbes in the lung, but physiological processes integrating responses across diverse cell types and organ systems dictate the outcome of respiratory infection. Resistance, or actions of the host to eradicate living microbes, in the lungs involves a combination of innate and adaptive immune responses triggered by air-space infection. Resilience, or the ability of the host tissues to withstand the physiologically damaging effects of microbial and immune activities, is equally complex, precisely regulated, and determinative. Both immune resistance and tissue resilience are dynamic and change throughout the lifetime, but we are only beginning to understand such remodeling and how it contributes to the incidence of severe pneumonias, which diminishes as childhood progresses and then increases again among the elderly. Here, we review the concepts of resistance, resilience, and remodeling as they apply to pneumonia, highlighting recent advances and current significant knowledge gaps.
The Neuroendocrinology of Social Isolation
Authors: Cacioppo John T. , Cacioppo Stephanie , Capitanio John P. , Cole Steven W.
Published: August 2014

Social isolation has been recognized as a major risk factor for morbidity and mortality in humans for more than a quarter of a century. Although the focus of research has been on objective social roles and health behavior, the brain is the key organ for forming, monitoring, maintaining, repairing, and replacing salutary connections with others. Accordingly, population-based longitudinal research indicates that perceived social isolation (loneliness) is a risk factor for morbidity and mortality independent of objective social isolation and health behavior. Human and animal investigations of neuroendocrine stress mechanisms that may be involved suggest that (a) chronic social isolation increases the activation of the hypothalamic pituitary adrenocortical axis, and (b) these effects are more dependent on the disruption of a social bond between a significant pair than objective isolation per se. The relational factors and neuroendocrine, neurobiological, and genetic mechanisms that may contribute to the association between perceived isolation and mortality are reviewed.
Advances in Mediation Analysis: A Survey and Synthesis of New Developments
Authors: Preacher Kristopher J.
Published: August 2014

Mediation processes are fundamental to many classic and emerging theoretical paradigms within psychology. Innovative methods continue to be developed to address the diverse needs of researchers studying such indirect effects. This review provides a survey and synthesis of four areas of active methodological research: (a) mediation analysis for longitudinal data, (b) causal inference for indirect effects, (c) mediation analysis for discrete and nonnormal variables, and (d) mediation assessment in multilevel designs. The aim of this review is to aid in the dissemination of developments in these four areas and suggest directions for future research.
Effects of Thoratec pulsatile ventricular assist device timing on the abdominal aortic wave intensity pattern
Authors: Jahren Silje Ekroll , Amacher Raffael , Weber Alberto , Most Henriette , Flammer Shannon Axiak , Traupe Tobias , Stoller Michael , de Marchi Stefano , Vandenberghe Stijn
Published: August 2014

Arterial waves are seen as possible independent mediators of cardiovascular risks, and the wave intensity analysis (WIA) has therefore been proposed as a method for patient selection for ventricular assist device (VAD) implantation. Interpreting measured wave intensity (WI) is challenging, and complexity is increased by the implantation of a VAD. The waves generated by the VAD interact with the waves generated by the native heart, and this interaction varies with changing VAD settings. Eight sheep were implanted with a pulsatile VAD (PVAD) through ventriculoaortic cannulation. The start of PVAD ejection was synchronized to the native R wave and delayed between 0 and 90% of the cardiac cycle in 10% steps or phase shifts (PS). Pressure and velocity signals were registered, with the use of a combined Doppler and pressure wire positioned in the abdominal aorta, and used to calculate the WI. Depending on the PS, different wave interference phenomena occurred. Maximum unloading of the left ventricle (LV) coincided with constructive interference and maximum blood flow pulsatility, and maximum loading of the LV coincided with destructive interference and minimum blood flow pulsatility. We believe that noninvasive WIA could potentially be used clinically to assess the mechanical load of the LV and to monitor the peripheral hemodynamics such as blood flow pulsatility and risk of intestinal bleeding.
Ultrasound imaging with bolus delivered contrast agent for the detection of angiogenesis and blood flow irregularities
Authors: Korpisalo Petra , Hytönen Jarkko P. , Laitinen Johannes T. T. , Närväinen Johanna , Rissanen Tuomas T. , Gröhn Olli H. , Ylä-Herttuala Seppo
Published: August 2014

Highly increased blood flow and vascularity after angiogenic gene therapy have raised concerns of shunting and hemangioma-like blood pool formation that might decrease effective perfusion and ruin the beneficial effects of the therapy. Contrast enhanced ultrasound is a promising noninvasive tool for studying skeletal muscle perfusion. The objectives of the present study were to test bolus and infusion administrations of ultrasound microbubble contrast media in imaging vascular growth in skeletal muscle and assess the functionality of vessels grown with angiogenic gene therapy. Contrast enhanced ultrasound was used to study changes in skeletal muscle perfusion in normal and gene-transduced rabbit hindlimbs 6 days after gene transfer. Adenoviral gene transfer of VEGF (10 e9–10 e11 viral particles) or β-galactosidase control gene (10 e11 viral particles) was done under anesthesia and induced up to 16-fold increases in relative tissue perfusion. Contrast intensity versus time curves were plotted and analyzed for contrast kinetics. Bolus administration of the contrast media was highly feasible in analyzing skeletal muscle blood flow and its kinetics. Maximal signal intensity of the bolus signal reflected relative changes in both blood flow and volume equally to the infusion method. Flow irregularities were detected after angiogenic gene therapy. In conclusion, bolus delivery of ultrasound contrast agent is highly feasible for the relative analysis of both quantity and quality of blood flow after angiogenic gene therapy. The kinetics of blood flow can and should be studied more extensively in both preclinical and clinical trials of angiogenic gene therapy since there is increasing evidence of flow irregularities in angiogenic vessels.
Propionate stimulates pyruvate oxidation in the presence of acetate
Authors: Purmal Colin , Kucejova Blanka , Sherry A. Dean , Burgess Shawn C. , Malloy Craig. R. , Merritt Matthew E.
Published: August 2014

Flux through pyruvate dehydrogenase (PDH) in the heart may be reduced by various forms of injury to the myocardium, or by oxidation of alternative substrates in normal heart tissue. It is important to distinguish these two mechanisms because imaging of flux through PDH based on the appearance of hyperpolarized (HP) [13C]bicarbonate derived from HP [1-13C]pyruvate has been proposed as a method for identifying viable myocardium. The efficacy of propionate for increasing PDH flux in the setting of PDH inhibition by an alternative substrate was studied using isotopomer analysis paired with exams using HP [1-13C]pyruvate. Hearts from C57/bl6 mice were supplied with acetate (2 mM) and glucose (8.25 mM).13C NMR spectra were acquired in a cryogenically cooled probe at 14.1 Tesla. After addition of hyperpolarized [1-13C]pyruvate,13C NMR signals from lactate, alanine, malate, and aspartate were easily detected, in addition to small signals from bicarbonate and CO2. The addition of propionate (2 mM) increased appearance of HP [13C]bicarbonate >30-fold without change in O2consumption. Isotopomer analysis of extracts from the freeze-clamped hearts indicated that acetate was the preferred substrate for energy production, glucose contribution to energy production was minimal, and anaplerosis was stimulated in the presence of propionate. Under conditions where production of acetyl-CoA is dominated by the availability of an alternative substrate, acetate, propionate markedly stimulated PDH flux as detected by the appearance of hyperpolarized [13C]bicarbonate from metabolism of hyperpolarized [1-13C]pyruvate.
Vascular dysfunction precedes hypertension associated with a blood pressure locus on rat chromosome 12
Authors: Prisco Sasha Z. , Priestley Jessica R. C. , Weinberg Brian D. , Prisco Anthony R. , Hoffman Matthew J. , Jacob Howard J. , Flister Michael J. , Lombard Julian H. , Lazar Jozef
Published: August 2014

We previously isolated a 6.1-Mb region of SS/Mcwi (Dahl salt-sensitive) rat chromosome 12 (13.4–19.5 Mb) that significantly elevated blood pressure (BP) (Δ+34 mmHg, P < 0.001) compared with the SS-12BN consomic control. In the present study, we examined the role of vascular dysfunction and remodeling in hypertension risk associated with the 6.1-Mb (13.4–19.5 Mb) locus on rat chromosome 12 by reducing dietary salt, which lowered BP levels so that there were no substantial differences in BP between strains. Consequently, any observed differences in the vasculature were considered BP-independent. We also reduced the candidate region from 6.1 Mb with 133 genes to 2 Mb with 23 genes by congenic mapping. Both the 2 Mb and 6.1 Mb congenic intervals were associated with hypercontractility and decreased elasticity of resistance vasculature prior to elevations of BP, suggesting that the vascular remodeling and dysfunction likely contribute to the pathogenesis of hypertension in these congenic models. Of the 23 genes within the narrowed congenic interval, 12 were differentially expressed between the resistance vasculature of the 2 Mb congenic and SS-12BN consomic strains. Among these, Grifin was consistently upregulated 2.7 ± 0.6-fold ( P < 0.05) and 2.0 ± 0.3-fold ( P < 0.01), and Chst12 was consistently downregulated −2.8 ± 0.3-fold ( P < 0.01) and −4.4 ± 0.4-fold ( P < 0.00001) in the 2 Mb congenic compared with SS-12BN consomic under normotensive and hypertensive conditions, respectively. A syntenic region on human chromosome 7 has also been associated with BP regulation, suggesting that identification of the genetic mechanism(s) underlying cardiovascular phenotypes in this congenic strain will likely be translated to a better understanding of human hypertension.
Intratracheal administration of cyclooxygenase-1-transduced adipose tissue-derived stem cells ameliorates monocrotaline-induced pulmonary hypertension in rats
Authors: Somanna Naveen K. , Wörner Philipp M. , Murthy Subramanyam N. , Pankey Edward A. , Schächtele Deborah J. , St. Hilaire Rose-Claire , Jansen David , Chaffin Abigail E. , Nossaman Bobby D. , Alt Eckhard U. , Kadowitz Philip J. , Izadpanah Reza
Published: August 2014

The effect of intratracheal administration of cyclooxygenase-1 (COX-1)-modified adipose stem cells (ASCs) on monocrotaline-induced pulmonary hypertension (MCT-PH) was investigated in the rat. The COX-1 gene was cloned from rat intestinal cells, fused with a hemagglutanin (HA) tag, and cloned into a lentiviral vector. The COX-1 lentiviral vector was shown to enhance COX-1 protein expression and inhibit proliferation of vascular smooth muscle cells without increasing apoptosis. Human ASCs transfected with the COX-1 lentiviral vector (ASCCOX-1) display enhanced COX-1 activity while exhibiting similar differentiation potential compared with untransduced (native) ASCs. PH was induced in rats with MCT, and the rats were subsequently treated with intratracheal injection of ASCCOX-1 or untransduced ASCs. The intratracheal administration of ASCCOX-1 3 × 106 cells on day 14 after MCT treatment significantly attenuated MCT-induced PH when hemodynamic values were measured on day 35 after MCT treatment whereas administration of untransduced ASCs had no significant effect. These results indicate that intratracheally administered ASCCOX-1 persisted for at least 21 days in the lung and attenuate MCT-induced PH and right ventricular hypertrophy. In addition, vasodilator responses to the nitric oxide donor sodium nitroprusside were not altered by the presence of ASCCOX-1 in the lung. These data emphasize the effectiveness of ASCCOX-1 in the treatment of experimentally induced PH.
Role of MMP2 and MMP9 in TRPV4-induced lung injury
Authors: Villalta Patricia C. , Rocic Petra , Townsley Mary I.
Published: August 2014

Ca2+entry through transient receptor potential vanilloid 4 (TRPV4) results in swelling, blebbing, and detachment of the epithelium and capillary endothelium in the intact lung. Subsequently, increased permeability of the septal barrier and alveolar flooding ensue. In this study, we tested the hypothesis that TRPV4 activation provides a Ca2+source necessary for proteolytic disruption of cell-cell or cell-matrix adhesion by matrix metalloproteinases (MMPs) 2 and 9, thus increasing septal barrier permeability. In our study, C57BL/6 or TRPV4−/−mouse lungs were perfused with varying doses of the TRPV4 agonist GSK-1016790A (Sigma) and then prepared for Western blot. Lung injury, assessed by increases in lung wet-to-dry weight ratios and total protein levels in the bronchoalveolar lavage fluid, was increased in a dose-dependent fashion in TRPV4+/+but not TRPV4−/−lungs. In concert with lung injury, we detected increased active MMP2 and MMP9 isoforms, suggesting that TRPV4 can provide the Ca2+source necessary for increased MMP2/9 activation. Furthermore, tissue inhibitor of metalloproteinases (TIMP) 2 levels in the TRPV4-injured lungs were decreased, suggesting that TRPV4 activation increases the availability of these active MMPs. We then determined whether MMP2 and MMP9 mediate TRPV4-induced lung injury. Pharmacological blockade (SB-3CT, 1 μM; Sigma) of MMP2 and MMP9 resulted in protection against TRPV4-induced lung injury. We conclude that TRPV4 activation and the subsequent Ca2+transient initiates a rapid cascade of events leading to release and activation of the gelatinase MMPs, which then contribute to lung injury.
Regulation of fibroblast lipid storage and myofibroblast phenotypes during alveolar septation in mice
Authors: McGowan Stephen E. , McCoy Diann M.
Published: August 2014

Signaling through platelet-derived growth factor receptor-α (PDGFRα) is required for alveolar septation and participates in alveolar regeneration after pneumonectomy. In both adipose tissue and skeletal muscle, bipotent pdgfrα-expressing progenitors expressing delta-like ligand-1 or sex-determining region Y box 9 (Sox9) may differentiate into either lipid storage cells or myofibroblasts. We analyzed markers of mesenchymal progenitors and differentiation in lung fibroblasts (LF) with different levels (absent, low, or high) of pdgfrα gene expression. A larger proportion of pdgfrα-expressing than nonexpressing LF contained Sox9. Neutral lipids, CD166, and Tcf21 were more abundant in LF with a lower compared with a higher level of pdgfrα gene expression. PDGF-A increased Sox9 in primary LF cultures, suggesting that active signaling through PDGFRα is required to maintain Sox9. As alveolar septation progresses from postnatal day (P) 8 to P12, fewer pdgfrα-expressing LF contain Sox9, whereas more of these LF contain myocardin-like transcription factor-A, showing that Sox9 diminishes as LF become myofibroblasts. At P8, neutral lipid droplets predominate in LF with the lower level of pdgfrα gene expression, whereas transgelin ( tagln) was predominantly expressed in LF with higher pdgfrα gene expression. Targeted deletion of pdgfrα in LF, which expressed tagln, reduced Sox9 in α-actin (α-SMA, ACTA2)-containing LF, whereas it increased the abundance of cell surface delta-like protein-1 (as well as peroxisome proliferator-activated receptor-γ and tcf21 mRNA in LF, which also expressed stem cell antigen-1). Thus pdgfrα deletion differentially alters delta-like protein-1 and Sox9, suggesting that targeting different downstream pathways in PDGF-A-responsive LF could identify strategies that promote lung regeneration without initiating fibrosis.
The genome-wide transcriptional response to neonatal hyperoxia identifies Ahr as a key regulator
Authors: Bhattacharya Soumyaroop , Zhou Zhongyang , Yee Min , Chu Chin-Yi , Lopez Ashley M. , Lunger Valerie A. , Solleti Siva Kumar , Resseguie Emily , Buczynski Bradley , Mariani Thomas J. , O'Reilly Michael A.
Published: August 2014

Premature infants requiring supplemental oxygen are at increased risk for developing bronchopulmonary dysplasia (BPD). Rodent models involving neonatal exposure to excessive oxygen concentrations (hyperoxia) have helped to identify mechanisms of BPD-associated pathology. Genome-wide assessments of the effects of hyperoxia in neonatal mouse lungs could identify novel BPD-related genes and pathways. Newborn C57BL/6 mice were exposed to 100% oxygen for 10 days, and whole lung tissue RNA was used for high-throughput, sequencing-based transcriptomic analysis (RNA-Seq). Significance Analysis of Microarrays and Ingenuity Pathway Analysis were used to identify genes and pathways affected. Expression patterns for selected genes were validated by qPCR. Mechanistic relationships between genes were further tested in cultured mouse lung epithelial cells. We identified 300 genes significantly and substantially affected following acute neonatal hyperoxia. Canonical pathways dysregulated in hyperoxia lungs included nuclear fctor (erythryoid-derived-2)-like 2-mediated oxidative stress signaling, p53 signaling, eNOS signaling, and aryl hydrocarbon receptor (Ahr) pathways. Cluster analysis identified Ccnd1, Cdkn1a, and Ahr as critical regulatory nodes in the response to hyperoxia, with Ahr serving as the major effector node. A mechanistic role for Ahr was assessed in lung epithelial cells, and we confirmed its ability to regulate the expression of multiple hyperoxia markers, including Cdkn1a, Pdgfrb, and A2m. We conclude that a global assessment of gene regulation in the acute neonatal hyperoxia model of BPD-like pathology has identified Ahr as one driver of gene dysregulation.
cAMP-dependent protein kinase activation decreases cytokine release in bronchial epithelial cells
Authors: Wyatt Todd A. , Poole Jill A. , Nordgren Tara M. , DeVasure Jane M. , Heires Art J. , Bailey Kristina L. , Romberger Debra J.
Published: August 2014

Lung injury caused by inhalation of dust from swine-concentrated animal-feeding operations (CAFO) involves the release of inflammatory cytokine interleukin 8 (IL-8), which is mediated by protein kinase C-ε (PKC-ε) in airway epithelial cells. Once activated by CAFO dust, PKC-ε is responsible for slowing cilia beating and reducing cell migration for wound repair. Conversely, the cAMP-dependent protein kinase (PKA) stimulates contrasting effects, such as increased cilia beating and an acceleration of cell migration for wound repair. We hypothesized that a bidirectional mechanism involving PKA and PKC regulates epithelial airway inflammatory responses. To test this hypothesis, primary human bronchial epithelial cells and BEAS-2B cells were treated with hog dust extract (HDE) in the presence or absence of cAMP. PKC-ε activity was significantly reduced in cells that were pretreated for 1 h with 8-bromoadenosine 3′,5′-cyclic monophosphate (8-Br-cAMP) before exposure to HDE ( P < 0.05). HDE-induced IL-6, and IL-8 release was significantly lower in cells that were pretreated with 8-Br-cAMP ( P < 0.05). To exclude exchange protein activated by cAMP (EPAC) involvement, cells were pretreated with either 8-Br-cAMP or 8-(4-chlorophenylthio)-2'- O-methyladenosine-3',5'-cyclic monophosphate (8-CPT-2Me-cAMP) (EPAC agonist). 8-CPT-2Me-cAMP did not activate PKA and did not reduce HDE-stimulated IL-6 release. In contrast, 8-Br-cAMP decreased HDE-stimulated tumor necrosis factor (TNF)-α-converting enzyme (TACE; ADAM-17) activity and subsequent TNF-α release ( P < 0.001). 8-Br-cAMP also blocked HDE-stimulated IL-6 and keratinocyte-derived chemokine release in precision-cut mouse lung slices ( P < 0.05). These data show bidirectional regulation of PKC-ε via a PKA-mediated inhibition of TACE activity resulting in reduced PKC-ε-mediated release of IL-6 and IL-8.
Postural disturbances resulting from unilateral and bilateral diaphragm contractions: a phrenic nerve stimulation study
Authors: Hamaoui Alain , Hudson Anna L. , Laviolette Louis , Nierat Marie-Cécile , Do Manh-Cuong , Similowski Thomas
Published: August 2014

Thoracoabdominal breathing movements are a complex source of postural disturbance, but there are contradictory reports in the literature with inspiration described as having either a backward or a forward disturbing effect. To elucidate the mechanisms underlying this phenomenon, the present study studied the postural disturbance caused by isolated contractions of the diaphragm. Eight male and four female healthy subjects followed an original paradigm of phrenic nerve stimulation (bilateral and unilateral) and “diaphragmatic” voluntary sniff maneuvers in the seated and standing postures. Center of gravity (CG) acceleration was calculated from force plate recordings, and respiratory kinematics were assessed with thoracic and abdominal sensor belts. CG and respiratory signals revealed that, while seated, bilateral phrenic stimulation and sniff maneuvers consistently produced expansion of the abdomen associated with a forward peak of CG acceleration. In the standing posture, the direction of the CG peak was reversed and always directed backward. Unilateral phrenic stimulation induced an additional medial-lateral acceleration of the CG, directed toward the nonactive side while seated, but in the opposite direction while standing. These results suggest that isolated diaphragmatic contractions produce a constant disturbing pattern for a given posture, but with opposite effects between standing and seated postures. This could be related to the different biomechanical configuration of the body in each posture, corresponding to distinct kinematic patterns of the osteoarticular chain. In addition, the lateral component of the CG acceleration induced by unilateral diaphragm contractions could be clinically relevant in patients with hemidiaphragm paralysis.
Participation in a 1,000-mile race increases the oxidation of carbohydrate in Alaskan sled dogs
Authors: Miller Benjamin F. , Drake Joshua C. , Peelor Frederick F. , Biela Laurie M. , Geor Raymond , Hinchcliff Kenneth , Davis Michael , Hamilton Karyn L.
Published: August 2014

The Alaskan Husky has been specifically bred for endurance performance and is capable of extreme endurance performance. We examined sled dogs in the trained state at the beginning of the race season and after a 1,600-km race (Iditarod). Our hypothesis was that lipids would be the predominant substrate during submaximal exercise in long-distance racing sled dogs, and a 1,600-km race would increase the reliance on lipids during an exercise bout at the same absolute exercise intensity. The experiments were completed over three testing periods, which were completed in January of two different years before participation in a 1,600-km race, or in March shortly after completion of a 1,600-km race. After determination of H13CO3−recovery, the dogs were tested with primed continuous infusions of [1,1,2,3,3-2H]glycerol, [3-13C]lactate, or [6,6-2H2]glucose. During exercise, respiratory exchange ratio was significantly higher in raced (0.92 ± 0.01) compared with nonraced (0.87 ± 0.01) dogs. During exercise, glucose rate of appearance was potentially sustained by a large glycerol rate of disappearance with an increase in lactate rates of oxidation after a 1,600-km race. Therefore, contrary to our hypothesis, the sled dogs were dependent on carbohydrate energy sources, a reliance that increased further after participation in a 1,600-km race.
Phosphodiesterase 4D Inhibitors Limit Prostate Cancer Growth Potential
Authors: Powers Ginny L. , Hammer Kimberly D.P. , Domenech Maribella , Frantskevich Katsiaryna , Malinowski Rita L. , Bushman Wade , Beebe David J. , Marker Paul C.
Published: August 2014

Phosphodiesterase 4D (PDE4D) has recently been implicated as a proliferation-promoting factor in prostate cancer and is overexpressed in human prostate carcinoma. However, the effects of PDE4D inhibition using pharmacologic inhibitors have not been examined in prostate cancer. These studies examined the effects of selective PDE4D inhibitors, NVP-ABE171 and cilomilast, as anti–prostate cancer therapies in both in vitro and in vivo models. The effects of PDE4D inhibitors on pathways that are critical in prostate cancer and/or downstream of cyclic AMP (cAMP) were examined. Both NVP-ABE171 and cilomilast decreased cell growth. In vitro, PDE4D inhibitors lead to decreased signaling of the sonic hedgehog (SHH), androgen receptor (AR), and MAPK pathways, but growth inhibition was best correlated to the SHH pathway. PDE4D inhibition also reduced proliferation of epithelial cells induced by paracrine signaling from cocultured stromal cells that had activated hedgehog signaling. In addition, PDE4D inhibitors decreased the weight of the prostate in wild-type mice. Prostate cancer xenografts grown in nude mice that were treated with cilomilast or NVP-ABE171 had decreased wet weight and increased apoptosis compared with vehicle-treated controls. These studies suggest the pharmacologic inhibition of PDE4D using small-molecule inhibitors is an effective option for prostate cancer therapy.

Implications: PDE4D inhibitors decrease the growth of prostate cancer cells in vivo and in vitro, and PDE4D inhibition has therapeutic potential in prostate cancer. Mol Cancer Res; 13(1); 149–60. ©2014 AACR.
Effects of Adiponectin on Calcium-Handling Proteins in Heart Failure With Preserved Ejection Fraction
Authors: Tanaka Komei , Wilson Richard M. , Essick Eric E. , Duffen Jennifer L. , Scherer Philipp E. , Ouchi Noriyuki , Sam Flora
Published: August 2014

Background—

Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF) in humans, there remains no therapeutic options for HFpEF. Adiponectin, an adipocyte-derived cytokine, exerts cardioprotective actions, and its deficiency is implicated in the development of hypertension and HF with reduced ejection fraction. Similarly, adiponectin deficiency in HFpEF exacerbates left ventricular hypertrophy, diastolic dysfunction, and HF. However, the therapeutic effects of adiponectin in HFpEF remain unknown. We sought to test the hypothesis that chronic adiponectin overexpression protects against the progression of HF in a murine model of HFpEF.

Methods and Results—

Adiponectin transgenic and wild-type mice underwent uninephrectomy, a continuous saline or
d
-aldosterone infusion and given 1.0% sodium chloride drinking water for 4 weeks. Aldosterone-infused wild-type mice developed HFpEF with hypertension, left ventricular hypertrophy, and diastolic dysfunction. Aldosterone infusion increased myocardial oxidative stress and decreased sarcoplasmic reticulum Ca
2+
-ATPase protein expression in HFpEF. Although total phospholamban protein expression was unchanged, there was a decreased expression of protein kinase A–dependent phospholamban phosphorylation at Ser16 and CaMKII (Ca
2+
/calmodulin-dependent protein kinase II)-dependent phospholamban phosphorylation at Thr17. Adiponectin overexpression in aldosterone-infused mice ameliorated left ventricular hypertrophy, diastolic dysfunction, lung congestion, and myocardial oxidative stress without affecting blood pressure and left ventricular EF. This improvement in diastolic dysfunction parameters in aldosterone-infused adiponectin transgenic mice was accompanied by the preserved protein expression of protein kinase A–dependent phosphorylation of phospholamban at Ser16. Adiponectin replacement prevented the progression of aldosterone-induced HFpEF, independent of blood pressure, by improving diastolic dysfunction and by modulating cardiac hypertrophy.

Conclusions—

These findings suggest that adiponectin may have therapeutic effects in patients with HFpEF.
Basigin Mediates Pulmonary Hypertension by Promoting Inflammation and Vascular Smooth Muscle Cell Proliferation
Authors: Satoh Kimio , Satoh Taijyu , Kikuchi Nobuhiro , Omura Junichi , Kurosawa Ryo , Suzuki Kota , Sugimura Koichiro , Aoki Tatsuo , Nochioka Kotaro , Tatebe Shunsuke , Miyamichi-Yamamoto Saori , Miura Masanobu , Shimizu Toru , Ikeda Shohei , Yaoita Nobuhiro , Fukumoto Yoshihiro , Minami Tatsuro , Miyata Satoshi , Nakamura Kazufumi , Ito Hiroshi , Kadomatsu Kenji , Shimokawa Hiroaki
Published: August 2014

Rationale:

Cyclophilin A (CyPA) is secreted from vascular smooth muscle cells (VSMCs) by oxidative stress and promotes VSMC proliferation. However, the role of extracellular CyPA and its receptor Basigin (Bsg, encoded by
Bsg
) in the pathogenesis of pulmonary hypertension (PH) remains to be elucidated.

Objective:

To determine the role of CyPA/Bsg signaling in the development of PH.

Methods and Results:

In the pulmonary arteries of patients with PH, immunostaining revealed strong expression of CyPA and Bsg. The pulmonary arteries of
CyPA
+/−
and
Bsg
+/−
mice exposed to normoxia did not differ in morphology compared with their littermate controls. In contrast,
CyPA
+/−
and
Bsg
+/−
mice exposed to hypoxia for 4 weeks revealed significantly reduced right ventricular systolic pressure, pulmonary artery remodeling, and right ventricular hypertrophy compared with their littermate controls. These features were unaltered by bone marrow reconstitution. To further evaluate the role of vascular Bsg, we harvested pulmonary VSMCs from
Bsg
+/+
and
Bsg
+/−
mice. Proliferation was significantly reduced in
Bsg
+/−
compared with
Bsg
+/+
VSMCs. Mechanistic studies demonstrated that
Bsg
+/−
VSMCs revealed reduced extracellular signal–regulated kinase 1/2 activation and less secretion of cytokines/chemokines and growth factors (eg, platelet-derived growth factor-BB). Finally, in the clinical study, plasma CyPA levels in patients with PH were increased in accordance with the severity of pulmonary vascular resistance. Furthermore, event-free curve revealed that high plasma CyPA levels predicted poor outcome in patients with PH.

Conclusions:

These results indicate the crucial role of extracellular CyPA and vascular Bsg in the pathogenesis of PH.
Diabetes Mellitus, Prediabetes, and Incidence of Subclinical Myocardial Damage
Authors: Selvin Elizabeth , Lazo Mariana , Chen Yuan , Shen Lu , Rubin Jonathan , McEvoy John W. , Hoogeveen Ron C. , Sharrett A. Richey , Ballantyne Christie M. , Coresh Josef
Published: August 2014

Background—

Persons with prediabetes and diabetes mellitus are at high risk for cardiovascular events. However, the relationships of prediabetes and diabetes mellitus to the development of subclinical myocardial damage are unclear.

Methods and Results—

We measured cardiac troponin T with a highly sensitive assay (hs-cTnT) at 2 time points, 6 years apart, among 9051 participants of the community-based Atherosclerosis Risk in Communities Study with no diabetes mellitus, or prediabetes, and without cardiovascular disease including silent myocardial infarction by ECG. First, we examined the incidence of elevated hs-cTnT (≥14 ng/L) at 6 years of follow-up. Second, we examined clinical outcomes during the subsequent ≈14 years of follow-up among persons with and without incident elevations in hs-cTnT. Cumulative probabilities of elevated hs-cTnT at 6 years among persons with no diabetes mellitus, prediabetes, and diabetes mellitus were 3.7%, 6.4%, and 10.8%, respectively. Compared with normoglycemic persons, the adjusted relative risks for incident elevated hs-cTnT were 1.40 (95% CI, 1.08–1.80) for prediabetes and 2.47 (95% CI, 1.78–3.43) for diabetes mellitus. Persons with diabetes mellitus and incident elevations in hs-cTnT were at a substantially higher risk of heart failure (hazard ratio, 6.37 [95% CI, 4.27–9.51]), death (hazard ratio, 4.36 [95% CI, 3.14–6.07]), and coronary heart disease (hazard ratio, 3.84 [95% CI, 2.52–5.84]) compared with persons without diabetes mellitus and no incident elevation in hs-cTnT.

Conclusions—

Prediabetes and diabetes mellitus were independently associated with the development of subclinical myocardial damage, as assessed by hs-cTnT, and those persons with evidence of subclinical damage were at highest risk for clinical events. These results support a possible deleterious effect of hyperglycemia on the myocardium, possibly reflecting a microvascular cause.
CD82 Restrains Pathological Angiogenesis by Altering Lipid Raft Clustering and CD44 Trafficking in Endothelial Cells
Authors: Wei Quan , Zhang Feng , Richardson Mekel M. , Roy Nathan H. , Rodgers William , Liu Yuechueng , Zhao Wenyuan , Fu Chenying , Ding Yingjun , Huang Chao , Chen Yuanjian , Sun Yao , Ding Lexi , Hu Yang , Ma Jian-Xing , Boulton Michael E. , Pasula Satish , Wren Jonathan D. , Tanaka Satoshi , Huang Xiaolin , Thali Markus , Hämmerling Günter J. , Zhang Xin A.
Published: August 2014

Background—

Angiogenesis is crucial for many pathological processes and becomes a therapeutic strategy against diseases ranging from inflammation to cancer. The regulatory mechanism of angiogenesis remains unclear. Although tetraspanin CD82 is widely expressed in various endothelial cells (ECs), its vascular function is unknown.

Methods and Results—

Angiogenesis was examined in
Cd82
-null mice with in vivo and ex vivo morphogenesis assays. Cellular functions, molecular interactions, and signaling were analyzed in
Cd82
-null ECs. Angiogenic responses to various stimuli became markedly increased upon
Cd82
ablation. Major changes in
Cd82
-null ECs were enhanced migration and invasion, likely resulting from the upregulated expression of cell adhesion molecules such as CD44 and integrins at the cell surface and subsequently elevated outside-in signaling. Gangliosides, lipid raft clustering, and CD44-membrane microdomain interactions were increased in the plasma membrane of
Cd82
-null ECs, leading to less clathrin-independent endocytosis and then more surface presence of CD44.

Conclusions—

Our study reveals that CD82 restrains pathological angiogenesis by inhibiting EC movement, that lipid raft clustering and cell adhesion molecule trafficking modulate angiogenic potential, that transmembrane protein modulates lipid rafts, and that the perturbation of CD82-ganglioside-CD44 signaling attenuates pathological angiogenesis.
A Hierarchical Adaptive Approach to Optimal Experimental Design
Authors: Kim Woojae , Pitt Mark A. , Lu Zhong-Lin , Steyvers Mark , Myung Jay I.
Published: August 2014

Experimentation is at the core of research in the behavioral and neural sciences, yet observations can be expensive and time-consuming to acquire (e.g., MRI scans, responses from infant participants). A major interest of researchers is designing experiments that lead to maximal accumulation of information about the phenomenon under study with the fewest possible number of observations. In addressing this challenge, statisticians have developed adaptive design optimization methods. This letter introduces a hierarchical Bayes extension of adaptive design optimization that provides a judicious way to exploit two complementary schemes of inference (with past and future data) to achieve even greater accuracy and efficiency in information gain. We demonstrate the method in a simulation experiment in the field of visual perception.
Noise Facilitation in Associative Memories of Exponential Capacity
Authors: Karbasi Amin , Salavati Amir Hesam , Shokrollahi Amin , Varshney Lav R.
Published: August 2014

Recent advances in associative memory design through structured pattern sets and graph-based inference algorithms have allowed reliable learning and recall of an exponential number of patterns that satisfy certain subspace constraints. Although these designs correct external errors in recall, they assume neurons that compute noiselessly, in contrast to the highly variable neurons in brain regions thought to operate associatively, such as hippocampus and olfactory cortex. Here we consider associative memories with boundedly noisy internal computations and analytically characterize performance. As long as the internal noise level is below a specified threshold, the error probability in the recall phase can be made exceedingly small. More surprising, we show that internal noise improves the performance of the recall phase while the pattern retrieval capacity remains intact: the number of stored patterns does not reduce with noise (up to a threshold). Computational experiments lend additional support to our theoretical analysis. This work suggests a functional benefit to noisy neurons in biological neuronal networks.
Delay Differential Analysis of Electroencephalographic Data
Authors: Lainscsek Claudia , Hernandez Manuel E. , Poizner Howard , Sejnowski Terrence J.
Published: August 2014

We propose a time-domain approach to detect frequencies, frequency couplings, and phases using nonlinear correlation functions. For frequency analysis, this approach is a multivariate extension of discrete Fourier transform, and for higher-order spectra, it is a linear and multivariate alternative to multidimensional fast Fourier transform of multidimensional correlations. This method can be applied to short and sparse time series and can be extended to cross-trial and cross-channel spectra (CTS) for electroencephalography data where multiple short data segments from multiple trials of the same experiment are available. There are two versions of CTS. The first one assumes some phase coherency across the trials, while the second one is independent of phase coherency. We demonstrate that the phase-dependent version is more consistent with event-related spectral perturbation analysis and traditional Morlet wavelet analysis. We show that CTS can be applied to short data windows and yields higher temporal resolution than traditional Morlet wavelet analysis. Furthermore, the CTS can be used to reconstruct the event-related potential using all linear components of the CTS.
A No-Go Theorem for One-Layer Feedforward Networks
Authors: Giusti Chad , Itskov Vladimir
Published: August 2014

It is often hypothesized that a crucial role for recurrent connections in the brain is to constrain the set of possible response patterns, thereby shaping the neural code. This implies the existence of neural codes that cannot arise solely from feedforward processing. We set out to find such codes in the context of one-layer feedforward networks and identified a large class of combinatorial codes that indeed cannot be shaped by the feedforward architecture alone. However, these codes are difficult to distinguish from codes that share the same sets of maximal activity patterns in the presence of subtractive noise. When we coarsened the notion of combinatorial neural code to keep track of only maximal patterns, we found the surprising result that all such codes can in fact be realized by one-layer feedforward networks. This suggests that recurrent or many-layer feedforward architectures are not necessary for shaping the (coarse) combinatorial features of neural codes. In particular, it is not possible to infer a computational role for recurrent connections from the combinatorics of neural response patterns alone. Our proofs use mathematical tools from classical combinatorial topology, such as the nerve lemma and the existence of an inverse nerve. An unexpected corollary of our main result is that any prescribed (finite) homotopy type can be realized by a subset of the form [Formula: see text], where [Formula: see text] is a polyhedron.