bluuebunny/crossref_metadata_2025 huggingface dataset:
Republished: The association between inflammatory markers, serum lipids and the risk of cardiovascular events in patients with rheumatoid arthritis
Authors: Zhang Jie , Chen Lang , Delzell Elizabeth , Muntner Paul , Hillegass William B , Safford Monika M , Millan Iris Yolanda Navarro , Crowson Cynthia S , Curtis Jeffrey R
Published: November 2014

Objective

To examine the association of serum inflammatory markers (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) and serum lipid measures (low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol) with risk of myocardial infarction (MI) and ischaemic stroke (IS) among rheumatoid arthritis (RA) patients.

Methods

We conducted a retrospective cohort study using 2005–2010 data from a US commercial health plan. Eligible patients had two or more physician diagnoses of RA during a baseline period of at least 180 days with continuous medical and pharmacy coverage. We computed age-adjusted incidence rates of MI and IS, and used spline regression to assess non-linear associations and Cox-regression to quantify the independent association between the laboratory values and the outcomes.

Results

We identified 44 418 eligible RA patients (mean age 49 years; 76% women). CRP>10 mg/L compared with <1 mg/L was associated with increased MI risk (HR 2.12; 95% CI 1.02 to 4.38). ESR>42 mm/h compared with <14 mm/h was associated with increased risk of MI (HR 2.53; 95% CI 1.48 to 4.31) and IS (HR 2.51; 95% CI 1.33 to 4.75) risk. HDL-cholesterol ≥60 mg/dL (1.6 mmol/L) compared with <40 mg/dL (1.0 mmol/L) was associated with reduced MI risk (HR 0.37; 0.21 to 0.66). The association between LDL and MI was not linear; the lowest risk was observed among patients with LDL between 70 mg/L (1.8 mmol/L) and 100 mg/L (2.6 mmol/L). We did not observe a significant association between LDL and IS.

Conclusions

This study provides evidence supporting the hypothesis that RA-related systemic inflammation plays a role in determining cardiovascular risk and a complex relationship between LDL and cardiovascular risk.
Republished: Cardiac MRI of patients with implanted electrical cardiac devices
Authors: Ainslie Mark , Miller Christopher , Brown Benjamin , Schmitt Matthias , Davidson Neil , Fox David J
Published: November 2014

Implantable pulse generators and defibrillators have traditionally been considered contraindications to MRI. However, recent data have challenged this paradigm and demonstrated that patients with newer generation devices can safely undergo MRI, including cardiac MRI, provided basic precautions are taken. Indeed, the introduction of MRI conditional systems has led to a conceptual shift in clinical decision making—‘can this patient undergo MRI safely?’ is being superseded by ‘should this patient be implanted with an MRI conditional device?’. This review outlines the risks associated with MRI in patients with implanted cardiac devices, and discusses practical measures to minimise risks and facilitate safe and diagnostic scanning.
Digital dermatitis treponemes associated with a severe foot disease in dairy goats
Authors: Sullivan L. E. , Evans N. J. , Clegg S. R. , Carter S. D. , Horsfield J. E. , Grove‐ White D. , Duncan J. S.
Published: November 2014

A UK dairy goat herd was assessed after reports of a severe lameness problem of unknown aetiology. A lameness prevalence estimate was produced and individual clinical examination of 15 randomly selected lame goats was performed. Fifteen animals had foot lesions closely resembling contagious ovine digital dermatitis (CODD) in sheep. Eight of the goats examined presented with typical CODD lesions and seven showed what appeared to be a more severe CODD with under‐running of the sole. Ten biopsy samples were obtained from the foot lesions and tested by PCR for the three previously isolated digital dermatitis (DD) Treponema phylogroups and culture of treponemes was attempted. Ninety per cent of the biopsy samples were positive for Treponema medium/Treponema vincentii ‐like spirochaetes and Treponema phagedenis‐ like DD spirochaetes and 80per cent were positive for Treponema pedis. Spirochaetes were successfully isolated from 50 per cent of lesion samples. Three isolates were identified as belonging to the T. phagedenis ‐like spirochaetes and two were identified as T. pedis. The frequent isolation of similar treponemes to those isolated from bovine digital dermatitis and CODD lesions and the identification of these DD‐associated phylotypes in the vast majority of lesions support the hypothesis that this novel foot condition is associated with infection by DD treponemes, and given the similarities to CODD, it suggests a causal role.
Localization of Aristolochic Acid in Mouse Kidney Tissues by Immunohistochemistry Using an Anti-AA-I and AA-II Monoclonal Antibody
Authors: Li Xiao-Wei , Yokota Sadaki , Wang Dan , Wang Xuan , Shoyama Yukihiro , Cai Shao-Qing
Published: November 2014

Aristolochic acids (AAs) are found in herbal medicines of Aristolochiaceae plants, including Aristolochia and Asarum species. AAs are associated with a rapidly progressive interstitial nephritis, which is called aristolochic acid nephropathy (AAN). However, the in-situ localization of AAs in the target organ, the kidney, has not been investigated yet. In the present study, the accumulation of aristolochic acid I (AA-I) in mouse kidney was revealed by immunoperoxidase light microscopy as well as colloidal gold immunoelectron microscopy (IEM) based on an anti-AA-I and AA-II monoclonal antibody (mAb). Male BALB/c mice were treated with 1.25 or 2.50 mg kg-1of AA-I per day for 5 days. Paraffin sections and ultra-thin sections of kidney tissue were respectively prepared. Under light microscopy, the apical surface of proximal tubules was strongly stained for AA-I, whereas no obvious immunostaining was found in the distal tubules and glomerulus, which remained relatively intact. Under electron microscopy, epithelial cells of the proximal tubules, distal tubules and collecting tubules were broken to various degrees. Gold labeling in the proximal and distal tubules was stronger than that in the collecting tubules. In renal tubules, immunogold signals of AA-I tended to accumulate in the mitochondria and peroxisomes, though the signals could be observed all over the cell. Gold signals were also found in the erythrocytes of glomeruli. The MAb against AA-I and AA-II provides a clue for the identification of proteins or factors which might interact with AA-I and thus induce targeted damage of kidney.
Denbinobin, a Phenanthrene fromDendrobium nobile, Impairs Prostate Cancer Migration by Inhibiting Rac1 Activity
Authors: Lu Te-Ling , Han Chien-Kuo , Chang Yuan-Shiun , Lu Te-Jung , Huang Hui-Chi , Bao Bo-Ying , Wu Hsing-Yu , Huang Chieh-Hung , Li Chia-Yen , Wu Tian-Shung
Published: November 2014

Prostate cancer is the most prevalent type of cancer in the United States. The most common site of prostate cancer metastasis is bone. CXCL12 is preferentially expressed in bone and is targeted by prostate cancer cells, which over-express the receptor for CXCL12, CXCR4. In response to CXCL12 stimulation, Rac1, a GTPase, along with its effectors, regulates actin polymerization to form lamellipodia, which is a critical event for cell migration. Cortactin, an actin-binding protein, is recruited to the lamellipodia and is phosphorylated at tyrosine residues. The phosphorylated cortactin is also involved in cell migration. The inhibition of Rac1 activity using a dominant negative Rac1 impairs lamellipodial protrusion as well as cortactin translocation and cortactin phosphorylation. Denbinobin, a substance extracted from Dendrobium nobile, has anticancer effects in many cancer cell lines. Whether denbinobin can inhibit prostate cancer cell migration is not clear. Here, we report that denbinobin inhibited Rac1 activity. The inhibition of Rac1 activity prevented lamellipodial formation. Cortactin phosphorylation and translocation to the lamellipodia were also impaired, and PC3 cells were unable to migrate. These results indicate that denbinobin prevents CXCL12-induced PC3 cell migration by inhibiting Rac1 activity.
Scheduling Trucks in Multi-Door Cross Docking Systems: An Adaptive Genetic Algorithm with a Dispatching Rule
Authors: Kim Byung Soo , Joo Cheol Min
Published: November 2014

One of the most important operational management problems of a cross docking system is the truck scheduling problem. Cross docking is a logistics management concept in which products delivered to a distribution center by inbound trucks are immediately sorted out, routed and loaded into outbound trucks for delivery to customers. The truck scheduling problem in a multi-door cross docking system considered in this paper comprises the assignment of trucks to dock doors and the determination of docking sequences for all inbound and outbound trucks in order to minimize the total operation time. A mathematical model for optimal solution is derived, and the genetic algorithms (GAs) and the adaptive genetic algorithms (AGAs) as solution approaches with different types of chromosomes are proposed. The performance of the meta-heuristic algorithms are evaluated using randomly generated several examples.
Remnants, fuzzballs or wormholes?
Authors: Mathur Samir D.
Published: November 2014

The black hole information paradox has caused enormous confusion over four decades. But in recent years, the theorem of quantum strong-subadditivity has sorted out the possible resolutions into three sharp categories: (i) No new physics at r ≫ lp; this necessarily implies remnants/information loss. A realization of remnants is given by a baby universe attached near r ~ 0. (ii) Violation of the "no-hair" theorem by nontrivial effects at the horizon r ~ M. This possibility is realized by fuzzballs in string theory, and gives unitary evaporation. (iii) Having the vacuum at the horizon, but requiring that Hawking quanta at r ~ M3 be somehow identified with degrees of freedom inside the black hole. A model for this "extreme nonlocality" is realized by conjecturing that wormholes connect the radiation quanta to the hole.
Kerr–Newman solution in modified teleparallel theory of gravity
Authors: Nashed Gamal G. L.
Published: November 2014

A nondiagonal tetrad field having six unknown functions plus an angle Φ, which is a function of the radial coordinate r, azimuthal angle θ and the polar angle ϕ, is applied to the charged field equations of modified teleparallel theory of gravity. A special nonvacuum solution is derived with three constants of integration. The tetrad field of this solution is axially symmetric and its scalar torsion is constant. The associated metric of the derived solution gives Kerr–Newman spacetime. We have shown that the derived solution can be described by a local Lorentz transformations plus a diagonal tetrad field that is the square root of the Kerr–Newman metric. We show that any solution of general relativity (GR) can be a solution in f(T) under certain conditions.
Dependence of the muon pseudorapidity on the cosmic ray mass composition around the knee
Authors: Rastegarzadeh Gohar , Nemati Mohammad
Published: November 2014

In order to identify the mass composition of cosmic rays (CRs), we have investigated the mean muon pseudorapidity (〈η〉) values of muonic component in extensive air showers (EASs). For this purpose we have simulated EASs by CORSIKA 7.4 code for Hydrogen, Oxygen and Iron nucleus. The energy range was selected between 1014 eV and 1016 eV with zenith angle from 0°–18°. We have compared our calculations with KASCADE muon tracking detector (MTD) measurements to obtain results on the primary mass relationship with mean muon pseudorapidity values of EASs muonic component. It is shown that after the knee energies, experimental data tend to the heavy primaries and mass composition becomes heavier. Finally, linear equations between the mass of primary and mean η values for different energies are obtained.
Vibrations of Axially Moving Vertical Rectangular Plates in Contact with Fluid
Authors: Wang Yan Qing , Xue Sen Wen , Huang Xiao Bo , Du Wei
Published: November 2014

The vibration characteristics of an axially moving vertical plate immersed in fluid and subjected to a pretension are investigated, with a special consideration to natural frequencies, complex mode functions and critical speeds of the system. The classical thin plate theory is adopted for the formulation of the governing equation of motion of the vibrating plates. The effects of free surface waves, compressibility and viscidity of the fluid are neglected in the analysis. The velocity potential and Bernoulli’s equation are used to describe the fluid pressure acting on the moving plate. The effect of fluid on the vibrations of the plate may be regarded as equivalent to an added mass on the plate. The formulation of added mass is obtained from kinematic boundary conditions of the plate–fluid interfaces. The effects of some system parameters such as the moving speed, stiffness ratios, location and aspect ratios of the plate and the fluid-plate density ratios on the above-mentioned vibration characteristics of the plate–fluid system are investigated in detail. Various different boundary conditions are considered in the study.
Practical Recommendations of Spectral Response Analysis in Non-Curved Alluvial Valleys Using Hybrid FE/BE Method
Authors: Gatmiri B. , Amini-Baneh D. , Dorostkar O. , Vakili M. R.
Published: November 2014

Most of researches consider seismic analysis using amplification of ground acceleration due to geotechnical effects. Many efforts also have been done to consider topographical effects in seismic analysis of alluvial valleys. Presented here is a new practical approach in spectral response of non-curved valleys which may be used as a simple method for considering topographical effects. A hybrid numerical approach which uses both FEM and BEM is conducted to study spectral acceleration increment due to geotechnical aspects in various topographical conditions. At first, spectral acceleration of non-curved valleys due to presence of sediments is investigated for various geometrical dimensions. The results show that the maximum value of normalized spectral acceleration response increases when the depth ratio of valleys increases. Practical criterion based on shape of configurations is presented to estimate normalized spectral acceleration. Finally geotechnical effects are quantified and a practical formulation is presented which cover all the conditions in non-curved valleys.
Regional hydrogeochemical mapping in Central Chile: natural and anthropogenic sources of elements and compounds
Authors: Jorquera Carmina O. , Oates Christopher J. , Plant Jane A. , Kyser Kurt , Ihlenfeld Christian , Voulvoulis Nikolaos
Published: November 2014

Geochemistry is a key tool in identifying sources of elements for both mineral exploration and environmental purposes. This study evaluates the first systematic regional hydrogeochemical survey for environmental assessments of the classic Andean copper mineral province and the Andina–Los Bronces mining district of Central Chile. One hundred and forty-five water samples were collected systematically in the Valparaíso and Metropolitana Regions of Central Chile, including the capital, Santiago. The concentrations of more than 70 elements and compounds were determined using inductively coupled plasma mass spectrometry (ICP-MS) and ion chromatography (IC) along with the stable isotopes (δD, δ
18
O, δ
34
S, δ
18
O
SO4
, δ
15
N and δ
18
O
NO3
) and used to define the geochemical baselines in the area and distinguish between different sources. The geochemistry demonstrates the potential to distinguish between natural (bedrock, hydrothermal alteration and mineralization) and anthropogenic (agriculture, sewage and urban) sources of elements. The distribution patterns of many chemicals show a strong correlation with the presence of evaporitic components (Ca, SO
4
2-
, Sr, K, Rb, total dissolved solids (TDS)), hydrothermal alteration and sulphide mineralization (Cu, Zn, Ni, Cd, Co and REEs). High concentrations of nitrate, phosphate and alkalinity occur downstream of agricultural areas and reflect pollution from fertilizers. Overall, the catchment areas affected by mining activities are relatively small and highly localized compared to those affected by agriculture and urban centres.

Supplementary material:

A list of anomalously high element concentrations and specific isotopic compositions associated by source is available at:
http://www.geolsoc.org.uk/SUP18799
Sodium entry through endothelial store-operated calcium entry channels: regulation by Orai1
Authors: Xu Ningyong , Cioffi Donna L. , Alexeyev Mikhail , Rich Thomas C. , Stevens Troy
Published: November 2014

Orai1 interacts with transient receptor potential protein of the canonical subfamily (TRPC4) and contributes to calcium selectivity of the endothelial cell store-operated calcium entry current ( ISOC). Orai1 silencing increases sodium permeability and decreases membrane-associated calcium, although it is not known whether Orai1 is an important determinant of cytosolic sodium transitions. We test the hypothesis that, upon activation of store-operated calcium entry channels, Orai1 is a critical determinant of cytosolic sodium transitions. Activation of store-operated calcium entry channels transiently increased cytosolic calcium and sodium, characteristic of release from an intracellular store. The sodium response occurred more abruptly and returned to baseline more rapidly than did the transient calcium rise. Extracellular choline substitution for sodium did not inhibit the response, although 2-aminoethoxydiphenyl borate and YM-58483 reduced it by ∼50%. After this transient response, cytosolic sodium continued to increase due to influx through activated store-operated calcium entry channels. The magnitude of this sustained increase in cytosolic sodium was greater when experiments were conducted in low extracellular calcium and when Orai1 expression was silenced; these two interventions were not additive, suggesting a common mechanism. 2-Aminoethoxydiphenyl borate and YM-58483 inhibited the sustained increase in cytosolic sodium, only in the presence of Orai1. These studies demonstrate that sodium permeates activated store-operated calcium entry channels, resulting in an increase in cytosolic sodium; the magnitude of this response is determined by Orai1.
The primary cilium as sensor of fluid flow: new building blocks to the model. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms
Authors: Praetorius Helle A.
Published: November 2014

The primary cilium is an extraordinary organelle. For many years, it had the full attention of only a few dedicated scientists fascinated by its uniqueness. Unexpectedly, after decades of obscurity, it has moved very quickly into the limelight with the increasing evidence of its central role in the many genetic variations that lead to what are now known as ciliopathies. These studies implicated unique biological functions of the primary cilium, which are not completely straightforward. In parallel, and initially completely unrelated to the ciliopathies, the primary cilium was characterized functionally as an organelle that makes cells more susceptible to changes in fluid flow. Thus the primary cilium was suggested to function as a flow-sensing device. This characterization has been substantiated for many epithelial cell types over the years. Nevertheless, part of the central mechanism of signal transduction has not been explained, largely because of the substantial technical challenges of working with this delicate organelle. The current review considers the recent advances that allow us to fill some of the holes in the model of signal transduction in cilium-mediated responses to fluid flow and to pursue the physiological implications of this peculiar organelle.
TASK-1 current is inhibited by phosphorylation during human and canine chronic atrial fibrillation
Authors: Harleton Erin , Besana Alessandra , Chandra Parag , Danilo Peter , Rosen Tove S. , Rosen Michael R. , Argenziano Michael , Robinson Richard B. , Feinmark Steven J.
Published: November 2014

Atrial fibrillation (AF) is a common arrhythmia with significant morbidities and only partially adequate therapeutic options. AF is associated with atrial remodeling processes, including changes in the expression and function of ion channels and signaling pathways. TWIK protein-related acid-sensitive K+ channel (TASK)-1, a two-pore domain K+ channel, has been shown to contribute to action potential repolarization as well as to the maintenance of resting membrane potential in isolated myocytes, and TASK-1 inhibition has been associated with the induction of perioperative AF. However, the role of TASK-1 in chronic AF is unknown. The present study investigated the function, expression, and phosphorylation of TASK-1 in chronic AF in atrial tissue from chronically paced canines and in human subjects. TASK-1 current was present in atrial myocytes isolated from human and canine hearts in normal sinus rhythm but was absent in myocytes from humans with AF and in canines after the induction of AF by chronic tachypacing. The addition of phosphatase to the patch pipette rescued TASK-1 current from myocytes isolated from AF hearts, indicating that the change in current is phosphorylation dependent. Western blot analysis showed that total TASK-1 protein levels either did not change or increased slightly in AF, despite the absence of current. In studies of perioperative AF, we have shown that phosphorylation of TASK-1 at Thr383 inhibits the channel. However, phosphorylation at this site was unchanged in atrial tissue from humans with AF or in canines with chronic pacing-induced AF. We conclude that phosphorylation-dependent inhibition of TASK-1 is associated with AF, but the phosphorylation site responsible for this inhibition remains to be identified.
Mending a broken heart: the role of mitophagy in cardioprotection
Authors: Moyzis Alexandra G. , Sadoshima Junichi , Gustafsson Åsa B.
Published: November 2014

The heart is highly energy dependent with most of its energy provided by mitochondrial oxidative phosphorylation. Mitochondria also play a role in many other essential cellular processes including metabolite synthesis and calcium storage. Therefore, maintaining a functional population of mitochondria is critical for cardiac function. Efficient degradation and replacement of dysfunctional mitochondria ensures cell survival, particularly in terminally differentiated cells such as cardiac myocytes. Mitochondria are eliminated via mitochondrial autophagy or mitophagy. In the heart, mitophagy is an essential housekeeping process and required for cardiac homeostasis. Reduced autophagy and accumulation of impaired mitochondria have been linked to progression of heart failure and aging. In this review, we discuss the pathways that regulate mitophagy in cells and highlight the cardioprotective role of mitophagy in response to stress and aging. We also discuss the therapeutic potential of targeting mitophagy and directions for future investigation.
Impact of chronic hypoxemia on blood flow to the brain, heart, and adrenal gland in the late-gestation IUGR sheep fetus
Authors: Poudel Rajan , McMillen I. Caroline , Dunn Stacey L. , Zhang Song , Morrison Janna L.
Published: November 2014

In the fetus, there is a redistribution of cardiac output in response to acute hypoxemia, to maintain perfusion of key organs, including the brain, heart, and adrenal glands. There may be a similar redistribution of cardiac output in the chronically hypoxemic, intrauterine growth-restricted fetus. Surgical removal of uterine caruncles in nonpregnant ewe results in the restriction of placental growth (PR) and intrauterine growth. Vascular catheters were implanted in seven control and six PR fetal sheep, and blood flow to organs was determined using microspheres. Placental and fetal weight was significantly reduced in the PR group. Despite an increase in the relative brain weight in the PR group, there was no difference in blood flow to the brain between the groups, although PR fetuses had higher blood flow to the temporal lobe. Adrenal blood flow was significantly higher in PR fetuses, and there was a direct relationship between mean gestational PaO2 and blood flow to the adrenal gland. There was no change in blood flow, but a decrease in oxygen and glucose delivery to the heart in the PR fetuses. In another group, there was a decrease in femoral artery blood flow in the PR compared with the Control group, and this may support blood flow changes to the adrenal and temporal lobe. In contrast to the response to acute hypoxemia, these data show that there is a redistribution of blood flow to the adrenals and temporal lobe, but not the heart or whole brain, in chronically hypoxemic PR fetuses in late gestation.
The earliest metanephric arteriolar progenitors and their role in kidney vascular development
Authors: Sequeira-Lopez Maria Luisa S. , Lin Eugene E. , Li Minghong , Hu Yan , Sigmund Curt D. , Gomez R. Ariel
Published: November 2014

The development of the kidney arterioles is poorly understood. Mature arterioles contain several functionally and morphologically distinct cell types, including smooth muscle, endothelial, and juxtaglomerular cells, and they are surrounded by interconnected pericytes, fibroblasts, and other interstitial cells. We have shown that the embryonic kidney possesses all of the necessary precursors for the development of the renal arterial tree, and those precursors assemble in situ to form the kidney arterioles. However, the identity of those precursors was unclear. Within the embryonic kidney, several putative progenitors marked by the expression of either the winged-forkhead transcription factor 1 (Foxd1+ progenitor), the aspartyl-protease renin (Ren+ progenitor), and/or hemangioblasts (Scl+ progenitor) are likely to differentiate and endow most of the cells of the renal arterial tree. However, the lineage relationships and the role of these distinct progenitors in renal vascular morphogenesis have not been delineated. We, therefore, designed a series of experiments to ascertain the hierarchical lineage relationships between Foxd1+ and Ren+ progenitors and the role of these two precursors in the morphogenesis and patterning of the renal arterial tree. Results show that 1) Foxd1+ cells are the precursors for all the mural cells (renin cells, smooth muscle cells, perivascular fibroblasts, and pericytes) of the renal arterial tree and glomerular mesangium, and 2) Foxd1 per se directs the origin, number, orientation, and cellular composition of the renal vessels.
AMP-activated protein kinase (AMPK) activation inhibits nuclear translocation of Smad4 in mesangial cells and diabetic kidneys
Authors: Zhao Jinghong , Miyamoto Satoshi , You Young-Hyun , Sharma Kumar
Published: November 2014

Diabetic nephropathy is characterized by diffuse mesangial matrix expansion and is largely dependent on the TGF-β/Smad signaling pathway. Smad4 is required for TGF-β signaling; however, its regulation has not been well characterized in diabetic kidney disease. Here, we report that high glucose is sufficient to stimulate nuclear translocation of Smad4 in mesangial cells and that stimulation of the major energy sensor AMP-activated protein kinase (AMPK) has a potent effect to block Smad4 nuclear translocation. Activation of AMPK by 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) inhibited high glucose-induced and TGF-β stimulation of nuclear Smad4. To identify which of the catalytic α-subunits may be involved, small interfering (si) RNA-based inhibition of AMPK α1- or α2-subunit was employed. Inhibition of either subunit reduced overall AMPK activity and contributed to Smad4 nuclear accumulation. In an animal model of early diabetic kidney disease, induction of diabetes was found to markedly stimulate Smad4 protein levels and enhance nuclear accumulation. AMPK activation with AICAR completely prevented the upregulation of Smad4 and reduced mesangial matrix accumulation. We conclude that stimulation of Smad4 in cell culture and in in vivo models of early diabetic kidney disease is dependent on AMPK.
Increased expression of p21WAF1/CIP1 in kidney proximal tubules mediates fibrosis
Authors: Megyesi Judit , Tarcsafalvi Adel , Li Shenyang , Hodeify Rawad , Seng Nang San Hti Lar , Portilla Didier , Price Peter M.
Published: November 2014

Tissue fibrosis is a major cause of death in developed countries. It commonly occurs after either acute or chronic injury and affects diverse organs, including the heart, liver, lung, and kidney. Using the renal ablation model of chronic kidney disease, we previously found that the development of progressive renal fibrosis was dependent on p21WAF1/Cip1 expression; the genetic knockout of the p21 gene greatly alleviated this disease. In the present study, we expanded on this observation and report that fibrosis induced by two different acute injuries to the kidney is also dependent on p21. In addition, when p21 expression was restricted only to the proximal tubule, fibrosis after injury was induced in the whole organ. One molecular fibrogenic switch we describe is transforming growth factor-β induction, which occurred in vivo and in cultured kidney cells exposed to adenovirus expressing p21. Our data suggests that fibrosis is p21 dependent and that preventing p21 induction after stress could be a novel therapeutic target.
Heliox breathing equally influences respiratory mechanics and cycling performance in trained males and females
Authors: Wilkie Sabrina S. , Dominelli Paolo B. , Sporer Benjamin C. , Koehle Michael S. , Sheel A. William
Published: November 2014

In this study we tested the hypothesis that inspiring a low-density gas mixture (helium-oxygen; HeO2) would minimize mechanical ventilatory constraints and preferentially increase exercise performance in females relative to males. Trained male ( n = 11, 31 yr) and female ( n = 10, 26 yr) cyclists performed an incremental cycle test to exhaustion to determine maximal aerobic capacity (V̇o2max; male = 61, female = 56 ml·kg−1·min−1). A randomized, single-blinded crossover design was used for two experimental days where subjects completed a 5-km cycling time trial breathing humidified compressed room air or HeO2(21% O2:balance He). Subjects were instrumented with an esophageal balloon for the assessment of respiratory mechanics. During the time trial, we assessed the ability of HeO2to alleviate mechanical ventilatory constraints in three ways: 1) expiratory flow limitation, 2) utilization of ventilatory capacity, and 3) the work of breathing. We found that HeO2significantly reduced the work of breathing, increased the size of the maximal flow-volume envelope, and reduced the fractional utilization of the maximal ventilatory capacity equally between men and women. The primary finding of this study was that inspiring HeO2was associated with a statistically significant performance improvement of 0.7% (3.2 s) for males and 1.5% (8.1 s) for females ( P < 0.05); however, there were no sex differences with respect to improvement in time trial performance ( P > 0.05). Our results suggest that the extent of sex-based differences in airway anatomy, work of breathing, and expiratory flow limitation is not great enough to differentially affect whole body exercise performance.
Differential sensitivity of oxidative and glycolytic muscles to hypoxia-induced muscle atrophy
Authors: de Theije C. C. , Langen R. C. J. , Lamers W. H. , Gosker H. R. , Schols A. M. W. J. , Köhler S. E.
Published: November 2014

Hypoxia as a consequence of acute and chronic respiratory disease has been associated with muscle atrophy. This study investigated the sensitivity of oxidative and glycolytic muscles to hypoxia-induced muscle atrophy. Male mice were exposed to 8% normobaric oxygen for up to 21 days. Oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles were isolated, weighed, and assayed for expression profiles of the ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), and glucocorticoid receptor (GR) and hypoxia-inducible factor-1α (HIF1α) signaling. Fiber-type composition and the capillary network were investigated. Hypoxia-induced muscle atrophy was more prominent in the EDL than the soleus muscle. Although increased expression of HIF1α target genes showed that both muscle types sensed hypoxia, their adaptive responses differed. Atrophy consistently involved a hypoxia-specific effect (i.e., not attributable to a hypoxia-mediated reduction of food intake) in the EDL only. Hypoxia-specific activation of the UPS and ALP and increased expression of the glucocorticoid receptor ( Gr) and its target genes were also mainly observed in the EDL. In the soleus, stimulation of gene expression of those pathways could be mimicked to a large extent by food restriction alone. Hypoxia increased the number of capillary contacts per fiber cross-sectional area in both muscles. In the EDL, this was due to type II fiber atrophy, whereas in the soleus the absolute number of capillary contacts increased. These responses represent two distinct modes to improve oxygen supply to muscle fibers, but may aggravate muscle atrophy in chronic obstructive pulmonary disease patients who have a predominance of type II fibers.
Simulating obstructive sleep apnea patients' oxygenation characteristics into a mouse model of cyclical intermittent hypoxia
Authors: Lim Diane C. , Brady Daniel C. , Po Pengse , Chuang Li Pang , Marcondes Laise , Kim Emily Y. , Keenan Brendan T. , Guo Xiaofeng , Maislin Greg , Galante Raymond J. , Pack Allan I.
Published: November 2014

Mouse models of cyclical intermittent hypoxia (CIH) are used to study the consequences of both hypoxia and oxidative stress in obstructive sleep apnea (OSA). Whether or not a mouse model of CIH that simulates OSA patients' oxygenation characteristics would translate into improved patient care remains unanswered. First we identified oxygenation characteristics using the desaturation and resaturation time in 47 OSA subjects from the Molecular Signatures of Obstructive Sleep Apnea Cohort (MSOSA). We observe that a cycle of intermittent hypoxia is not sinusoidal; specifically, desaturation time increases in an almost linear relationship to the degree of hypoxia (nadir), whereas resaturation time is somewhat constant (∼15 s), irrespective of the nadir. Second, we modified the Hycon mouse model of CIH to accommodate a 15-s resaturation time. Using this modified CIH model, we explored whether a short resaturation schedule (15 s), which includes the characteristics of OSA patients, had a different effect on levels of oxidative stress (i.e., urinary 8,12- iso-iPF2α-VI levels) compared with sham and a long resaturation schedule (90 s), a schedule that is not uncommon in rodent models of CIH. Results suggest that shorter resaturation time may result in a higher level of 8,12- iso-iPF2α-VI compared with long resaturation or sham conditions. Therefore, simulating the rodent model of CIH to reflect this and other OSA patients' oxygenation characteristics may be worthy of consideration to better understand the effects of hypoxia, oxidative stress, and their interactions.
Online gain update for manual following response accompanied by gaze shift during arm reaching
Authors: Abekawa Naotoshi , Gomi Hiroaki
Published: November 2014

To capture objects by hand, online motor corrections are required to compensate for self-body movements. Recent studies have shown that background visual motion, usually caused by body movement, plays a significant role in such online corrections. Visual motion applied during a reaching movement induces a rapid and automatic manual following response (MFR) in the direction of the visual motion. Importantly, the MFR amplitude is modulated by the gaze direction relative to the reach target location (i.e., foveal or peripheral reaching). That is, the brain specifies the adequate visuomotor gain for an online controller based on gaze-reach coordination. However, the time or state point at which the brain specifies this visuomotor gain remains unclear. More specifically, does the gain change occur even during the execution of reaching? In the present study, we measured MFR amplitudes during a task in which the participant performed a saccadic eye movement that altered the gaze-reach coordination during reaching. The results indicate that the MFR amplitude immediately after the saccade termination changed according to the new gaze-reach coordination, suggesting a flexible online updating of the MFR gain during reaching. An additional experiment showed that this gain updating mostly started before the saccade terminated. Therefore, the MFR gain updating process would be triggered by an ocular command related to saccade planning or execution based on forthcoming changes in the gaze-reach coordination. Our findings suggest that the brain flexibly updates the visuomotor gain for an online controller even during reaching movements based on continuous monitoring of the gaze-reach coordination.
Precise feedback control underlies sensorimotor learning in speech
Authors: Vaughn Chris , Nasir Sazzad M.
Published: November 2014

Acquiring the skill of speaking in another language, or for that matter a child's learning to talk, does not follow a single recipe. People learn by variable amounts. A major component of speech learnability seems to be sensing precise feedback errors to correct subsequent utterances that help maintain speech goals. We have tested this idea in a speech motor learning paradigm under altered auditory feedback, in which subjects repeated a word while their auditory feedback was changed online. Subjects learned the task to variable degrees, with some simply failing to learn. We assessed feedback contribution by computing one-lag covariance between formant trajectories of the current feedback and the following utterance that was found to be a significant predictor of learning. Our findings rely on a novel use of information-rich formant trajectories in evaluating speech motor learning and argue for their relevance in auditory speech goals of vowel sounds.
HCN channels contribute to serotonergic modulation of ventral surface chemosensitive neurons and respiratory activity
Authors: Hawkins Virginia E. , Hawryluk Joanna M. , Takakura Ana C. , Tzingounis Anastasios V. , Moreira Thiago S. , Mulkey Daniel K.
Published: November 2014

Chemosensitive neurons in the retrotrapezoid nucleus (RTN) provide a CO2/H+-dependent drive to breathe and function as an integration center for the respiratory network, including serotonergic raphe neurons. We recently showed that serotonergic modulation of RTN chemoreceptors involved inhibition of KCNQ channels and activation of an unknown inward current. Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels are the molecular correlate of the hyperpolarization-activated inward current ( Ih) and have a high propensity for modulation by serotonin. To investigate whether HCN channels contribute to basal activity and serotonergic modulation of RTN chemoreceptors, we characterize resting activity and the effects of serotonin on RTN chemoreceptors in vitro and on respiratory activity of anesthetized rats in the presence or absence of blockers of KCNQ (XE991) and/or HCN (ZD7288, Cs+) channels. We found in vivo that bilateral RTN injections of ZD7288 increased respiratory activity and in vitro HCN channel blockade increased activity of RTN chemoreceptors under control conditions, but this was blunted by KCNQ channel inhibition. Furthermore, in vivo unilateral RTN injection of XE991 plus ZD7288 eliminated the serotonin response, and in vitro serotonin sensitivity was eliminated by application of XE991 and ZD7288 or SQ22536 (adenylate cyclase blocker). Serotonin-mediated activation of RTN chemoreceptors was blocked by a 5-HT7-receptor blocker and mimicked by a 5-HT7-receptor agonist. In addition, serotonin caused a depolarizing shift in the voltage-dependent activation of Ih. These results suggest that HCN channels contribute to resting chemoreceptor activity and that serotonin activates RTN chemoreceptors and breathing in part by a 5-HT7receptor-dependent mechanism and downstream activation of Ih.
Sensitivity to timing and order in human visual cortex
Authors: Singer Jedediah M. , Madsen Joseph R. , Anderson William S. , Kreiman Gabriel
Published: November 2014

Visual recognition takes a small fraction of a second and relies on the cascade of signals along the ventral visual stream. Given the rapid path through multiple processing steps between photoreceptors and higher visual areas, information must progress from stage to stage very quickly. This rapid progression of information suggests that fine temporal details of the neural response may be important to the brain's encoding of visual signals. We investigated how changes in the relative timing of incoming visual stimulation affect the representation of object information by recording intracranial field potentials along the human ventral visual stream while subjects recognized objects whose parts were presented with varying asynchrony. Visual responses along the ventral stream were sensitive to timing differences as small as 17 ms between parts. In particular, there was a strong dependency on the temporal order of stimulus presentation, even at short asynchronies. From these observations we infer that the neural representation of complex information in visual cortex can be modulated by rapid dynamics on scales of tens of milliseconds.
Microchip amplifier for in vitro, in vivo, and automated whole cell patch-clamp recording
Authors: Harrison Reid R. , Kolb Ilya , Kodandaramaiah Suhasa B. , Chubykin Alexander A. , Yang Aimei , Bear Mark F. , Boyden Edward S. , Forest Craig R.
Published: November 2014

Patch clamping is a gold-standard electrophysiology technique that has the temporal resolution and signal-to-noise ratio capable of reporting single ion channel currents, as well as electrical activity of excitable single cells. Despite its usefulness and decades of development, the amplifiers required for patch clamping are expensive and bulky. This has limited the scalability and throughput of patch clamping for single-ion channel and single-cell analyses. In this work, we have developed a custom patch-clamp amplifier microchip that can be fabricated using standard commercial silicon processes capable of performing both voltage- and current-clamp measurements. A key innovation is the use of nonlinear feedback elements in the voltage-clamp amplifier circuit to convert measured currents into logarithmically encoded voltages, thereby eliminating the need for large high-valued resistors, a factor that has limited previous attempts at integration. Benchtop characterization of the chip shows low levels of current noise [1.1 pA root mean square (rms) over 5 kHz] during voltage-clamp measurements and low levels of voltage noise (8.2 μV rms over 10 kHz) during current-clamp measurements. We demonstrate the ability of the chip to perform both current- and voltage-clamp measurement in vitro in HEK293FT cells and cultured neurons. We also demonstrate its ability to perform in vivo recordings as part of a robotic patch-clamping system. The performance of the patch-clamp amplifier microchip compares favorably with much larger commercial instrumentation, enabling benchtop commoditization, miniaturization, and scalable patch-clamp instrumentation.
Substitution of extracellular Ca2+ by Sr2+ prolongs inspiratory burst in pre-Bötzinger complex inspiratory neurons
Authors: Morgado-Valle Consuelo , Fernandez-Ruiz Juan , Lopez-Meraz Leonor , Beltran-Parrazal Luis
Published: November 2014

The pre-Bötzinger complex (preBötC) underlies inspiratory rhythm generation. As a result of network interactions, preBötC neurons burst synchronously to produce rhythmic premotor inspiratory activity. Each inspiratory burst consists of action potentials (APs) on top of a 10- to 20-mV synchronous depolarization lasting 0.3–0.8 s known as inspiratory drive potential. The mechanisms underlying the initiation and termination of the inspiratory burst are unclear, and the role of Ca2+ is a matter of intense debate. To investigate the role of extracellular Ca2+ in inspiratory burst initiation and termination, we substituted extracellular Ca2+ with Sr2+. We found for the first time an ionic manipulation that significantly interferes with burst termination. In a rhythmically active slice, we current-clamped preBötC neurons ( Vm ≅ −60 mV) while recording integrated hypoglossal nerve (∫XIIn) activity as motor output. Substitution of extracellular Ca2+ with either 1.5 or 2.5 mM Sr2+ significantly prolonged the duration of inspiratory bursts from 653.4 ± 30.7 ms in control conditions to 981.6 ± 78.5 ms in 1.5 mM Sr2+ and 2,048.2 ± 448.5 ms in 2.5 mM Sr2+, with a concomitant increase in decay time and area. Substitution of extracellular Ca2+ by Sr2+ is a well-established method to desynchronize neurotransmitter release. Our findings suggest that the increase in inspiratory burst duration is determined by a presynaptic mechanism involving desynchronization of glutamate release within the network.
Do pursuit movement tasks lead to differential changes in early somatosensory evoked potentials related to motor learning compared with typing tasks?
Authors: Andrew Danielle , Yielder Paul , Murphy Bernadette
Published: November 2014

Central nervous system (CNS) plasticity is essential for development; however, recent research has demonstrated its role in pathology, particularly following overuse and repetition. Previous studies investigating changes in sensorimotor integration (SMI) have used relatively simple paradigms resulting in minimal changes in neural activity, as determined through the use of somatosensory evoked potentials (SEPs). This study sought to utilize complex tasks and compare separate motor paradigms to determine which one best facilitates long-term learning. Spinal, brainstem, and cortical SEPs were recorded following median nerve stimulation at the wrist pre- and postinterventions. Eighteen participants performed the same paradigms, a control condition of 10 min of mental recitation and two interventions, one consisting of 10 min of tracing and the other 10 min of repetitive typing. Significant increases in the N13, N20, P25, and N30 SEP peaks were seen for both interventions. A significant decrease in the N24 SEP peak was observed for both interventions. Significant improvements in accuracy were seen for both interventions postacquisition but only for tracing during retention. The changes seen following motor learning were congruent with those associated with long-term learning, which was also reflected by significant increases in accuracy during retention. Tracing or the pursuit movement paradigm was shown to be a more effective learning tool. The identification of a task that is sufficiently novel and complex, leading to robust changes in SEP peaks, indicates a task that can be utilized in future work to study clinical populations and the effect of experimental interventions on SMI.