The Journal of Physiology

Cover image for Vol. 594 Issue 3

Early View (Online Version of Record published before inclusion in an issue)

Edited By: David Paterson

Impact Factor: 5.037

ISI Journal Citation Reports © Ranking: 2014: 5/83 (Physiology); 41/252 (Neurosciences)

Online ISSN: 1469-7793

Associated Title(s): Experimental Physiology

VIEW

  1. 1 - 100
  2. 101 - 128
  1. Cardiovascular

    1. hERG quality control and the long QT syndrome

      Brian Foo, Brittany Williamson, Jason C. Young, Gergely Lukacs and Alvin Shrier

      Article first published online: 9 FEB 2016 | DOI: 10.1113/JP270531

      Thumbnail image of graphical abstract

      hERG cellular processing and quality control. Nascent hERG channels are inserted into the endoplasmic reticulum membrane where they undergo N-linked glycosylation. Properly folded hERG is exported to the Golgi apparatus where there is additional glycosylation prior to export to the plasma membrane (PM). Nascent hERG channels that fail to fold properly are targeted for Endoplasmic Reticulum Associated Degradation (ERAD). PM resident hERG channels are internalized and either cycled back to the PM or, if misfolded, are targeted for lysosomal degradation.

  2. Neuroscience - cellular/molecular

    1. Single CA3 pyramidal cells trigger sharp waves in vitro by exciting interneurones

      Michaël Bazelot, Maria T. Teleńczuk and Richard Miles

      Article first published online: 9 FEB 2016 | DOI: 10.1113/JP271644

      Key points

      • The CA3 hippocampal region generates sharp waves (SPW), a population activity associated with neuronal representations. The synaptic mechanisms responsible for the generation of these events still require clarification.
      • Using slices maintained in an interface chamber, we found that the firing of single CA3 pyramidal cells triggers SPW like events at short latencies, similar to those for the induction of firing in interneurons.
      • Multi-electrode records from the CA3 stratum pyramidale showed that pyramidal cells triggered events consisting of putative interneuron spikes followed by field IPSPs. SPW fields consisted of a repetition of these events at intervals of 4–8 ms. Although many properties of induced and spontaneous SPWs were similar, the triggered events tended to be initiated close to the stimulated cell.
      • These data show that the initiation of SPWs in vitro is mediated via pyramidal cell synapses that excite interneurons. They do not indicate why interneuron firing is repeated during a SPW.
  3. Integrative

    1. Individual variability of cerebral autoregulation, posterior cerebral circulation and white matter hyperintensity

      Jie Liu, Benjamin Y. Tseng, Muhammad Ayaz Khan, Takashi Tarumi, Candace Hill, Niki Mirshams, Timea M. Hodics, Linda S. Hynan and Rong Zhang

      Article first published online: 9 FEB 2016 | DOI: 10.1113/JP271068

      Key points

      • Cerebral autoregulation (CA) is a key mechanism to protect brain perfusion in the face of changes in arterial blood pressure, but little is known about individual variability of CA and its relationship to the presence of brain white matter hyperintensity (WMH) in older adults, a type of white matter lesion related to cerebral small vessel disease (SVD).
      • This study demonstrated the presence of large individual variability of CA in healthy older adults during vasoactive drug-induced changes in arterial pressure assessed at the internal carotid and vertebral arteries. We also observed, unexpectedly, that it was the ‘over-’ rather than the ‘less-reactive’ CA measured at the vertebral artery that was associated with WMH severity.
      • These findings challenge the traditional concept of CA and suggest that the presence of cerebral SVD, manifested as WMH, is associated with posterior brain hypoperfusion during acute increase in arterial pressure.
    2. Age protects from harmful effects produced by chronic intermittent hypoxia

      M. Quintero, E. Olea, S. V. Conde, A. Obeso, T. Gallego-Martin, C. Gonzalez, J. M. Monserrat, A. Gómez-Niño, S. Yubero and T. Agapito

      Article first published online: 9 FEB 2016 | DOI: 10.1113/JP270878

      Key points

      • Episodes of intermittent hypoxia, as produced in obstructive sleep apnoea, cause a carotid-driven sympathetic hyperactivity and an oxidative status leading to cardiovascular and metabolic pathologies, which are less pronounced in patients >60–65 years old.
      • In young rats (3–4 months) chronic intermittent hypoxia augments carotid body hypoxic responses, plasma catecholamine, renal catecholamine content and turnover, produces an oxidative status, and causes hypertension.
      • In aged rats (22–24 months) chronic intermittent hypoxia does not alter carotid body responses, catecholamine-related parameters or redox status, and does not cause hypertension.
      • It is concluded that age affords protection to harmful effects produced by chronic intermittent hypoxia.
      • Possible mechanisms involved in age protection and the significance of our findings in the diagnosis and therapeutic approaches to obstructive sleep apneoa in the elderly are considered.
  4. Molecular & cellular

    1. Shear stress activates monovalent cation channel transient receptor potential melastatin subfamily 4 in rat atrial myocytes via type 2 inositol 1,4,5-trisphosphate receptors and Ca2+ release

      Min-Jeong Son, Joon-Chul Kim, Sung Woo Kim, Bojjibabu Chidipi, Jeyaraj Muniyandi, Thoudam Debraj Singh, Insuk So, Krishna P. Subedi and Sun-Hee Woo

      Article first published online: 9 FEB 2016 | DOI: 10.1113/JP270887

      Key points

      • During each contraction and haemodynamic disturbance, cardiac myocytes are subjected to fluid shear stress as a result of blood flow and the relative movement of sheets of myocytes.
      • The present study aimed to characterize the shear stress-sensitive membrane current in atrial myocytes using the whole-cell patch clamp technique, combined with pressurized fluid flow, as well as pharmacological and genetic interventions of specific proteins.
      • The data obtained suggest that shear stress indirectly activates the monovalent cation current carried by transient receptor potential melastatin subfamily 4 channels via type 2 inositol 1,4,5-trisphosphate receptor-mediated Ca2+ release in subsarcolemmal domains of atrial myocytes.
      • Ca2+-mediated interactions between these two proteins under shear stress may be an important mechanism by which atrial cells measure mechanical stress and translate it to alter their excitability.
  5. Cardiovascular

    1. Developmental aspects of a life course approach to healthy ageing

      M. A. Hanson, C. Cooper, A. Aihie Sayer, R. J. Eendebak, G. F. Clough and J. R. Beard

      Article first published online: 4 FEB 2016 | DOI: 10.1113/JP270579

      Thumbnail image of graphical abstract

      The life course model of ageing showing average hypothetical trajectories of functional capacity for organs and systems in individuals from low (red) and high (blue) income settings. Low income settings are associated with a poorer start to life in terms of inherited health capital. Functional capacity develops more slowly in a low income setting, but reaches a lower peak capacity earlier in the life course. Throughout life the environmental challenges to function are likely to be greater in the low income setting, leading to faster and earlier decline. In addition, an acute challenge such as an accident or infection in mid-life may produce a dip in function followed by recovery in a high income setting, but a drastic loss of function in a low income setting (dashed red line). Provision of personal care, most often in high income settings, can slow the rate of decline, sustaining resilience in a manner similar to plasticity (dashed blue line).

  6. Muscle

    1. Modelling in vivo creatine/phosphocreatine in vitro reveals divergent adaptations in human muscle mitochondrial respiratory control by ADP after acute and chronic exercise

      Mia Ydfors, Meghan C. Hughes, Robert Laham, Uwe Schlattner, Jessica Norrbom and Christopher G. R. Perry

      Article first published online: 4 FEB 2016 | DOI: 10.1113/JP271259

      Key points

      • Mitochondrial respiratory sensitivity to ADP is thought to influence muscle fitness and is partly regulated by cytosolic–mitochondrial diffusion of ADP or phosphate shuttling via creatine/phosphocreatine (Cr/PCr) through mitochondrial creatine kinase (mtCK).
      • Previous measurements of respiration in vitro with Cr (saturate mtCK) or without (ADP/ATP diffusion) show mixed responses of ADP sensitivity following acute exercise vs. less sensitivity after chronic exercise.
      • In human muscle, modelling in vivo ‘exercising’ [Cr:PCr] during in vitro assessments revealed novel responses to exercise that differ from detections with or without Cr (±Cr).
      • Acute exercise increased ADP sensitivity when measured without Cr but had no effect ±Cr or with +Cr:PCr, whereas chronic exercise increased sensitivity ±Cr but lowered sensitivity with +Cr:PCr despite increased markers of mitochondrial oxidative capacity.
      • Controlling in vivo conditions during in vitro respiratory assessments reveals responses to exercise that differ from typical ±Cr comparisons and challenges our understanding of how exercise improves metabolic control in human muscle.
  7. Computational physiology and modelling

    1. Improving cardiomyocyte model fidelity and utility via dynamic electrophysiology protocols and optimization algorithms

      Trine Krogh-Madsen, Eric A. Sobie and David J. Christini

      Article first published online: 4 FEB 2016 | DOI: 10.1113/JP270618

      Thumbnail image of graphical abstract

      The process of estimating parameters in cardiac myocyte models can be improved by matching model output to complex objectives, such as irregularly timed action potentials and carefully designed voltage-clamp protocols. When combined with a global search heuristic, rather than manual parameter tuning, models can be generated that are more accurate and specific to individual cells.

  8. Neuroscience - behavioural/systems/cognitive

    1. Pre-emptive analgesia and its supraspinal mechanisms: enhanced descending inhibition and decreased descending facilitation by dexmedetomidine

      Hao-Jun You, Jing Lei, Ying Xiao, Gang Ye, Zhi-Hong Sun, Lan Yang and Nan Niu

      Article first published online: 4 FEB 2016 | DOI: 10.1113/JP271991

      Key points

      • Despite the clinical importance of pre-emptive analgesia, the mechanisms by which it attenuates pain associated with central sensitization are poorly understood.
      • We find that fentanyl and the α2-adrenoceptor agonist dexmedetomidine (Dex) differ significantly in their modulatory actions on noxious mechanical and noxious heat-evoked nociception in vivo.
      • Unlike fentanyl, Dex modified descending control of nociception by decreasing the threshold for descending inhibition and/or increasing the threshold for descending facilitation.
      • Dex exhibited after-actions on activities of thalamus in prolongation of noxious heat-evoked paw withdrawal latency that persisted for at least 7 days.
      • This study provides insight into the organization of thalamic modulation in pre-emptive analgesia.
  9. Muscle

    1. The involvement of transient receptor potential canonical type 1 in skeletal muscle regrowth after unloading-induced atrophy

      Lu Xia, Kwok-Kuen Cheung, Simon S. Yeung and Ella W. Yeung

      Article first published online: 4 FEB 2016 | DOI: 10.1113/JP271705

      Key points

      • Decreased mechanical loading results in skeletal muscle atrophy. The transient receptor potential canonical type 1 (TRPC1) protein is implicated in this process. Investigation of the regulation of TRPC1 in vivo has rarely been reported. In the present study, we employ the mouse hindlimb unloading and reloading model to examine the involvement of TRPC1 in the regulation of muscle atrophy and regrowth, respectively.
      • We establish the physiological relevance of the concept that manipulation of TRPC1 could interfere with muscle regrowth processes following an atrophy-inducing event. Specifically, we show that suppressing TRPC1 expression during reloading impairs the recovery of the muscle mass and slow myosin heavy chain profile. Calcineurin appears to be part of the signalling pathway involved in the regulation of TRPC1 expression during muscle regrowth.
      • These results provide new insights concerning the function of TRPC1. Interventions targeting TRPC1 or its downstream or upstream pathways could be useful for promoting muscle regeneration.
  10. Cardiovascular

    1. You have full text access to this OnlineOpen article
      Protection against ventricular fibrillation via cholinergic receptor stimulation and the generation of nitric oxide

      Manish Kalla, Minesh Chotalia, Charles Coughlan, Gouliang Hao, Mark J. Crabtree, Jakub Tomek, Gil Bub, David J. Paterson and Neil Herring

      Article first published online: 4 FEB 2016 | DOI: 10.1113/JP271588

      Key points

      • Animal studies suggest an anti-fibrillatory action of the vagus nerve on the ventricle, although the exact mechanism is controversial.
      • Using a Langendorff perfused rat heart, we show that the acetylcholine analogue carbamylcholine raises ventricular fibrillation threshold (VFT) and flattens the electrical restitution curve.
      • The anti-fibrillatory action of carbamylcholine was prevented by the nicotinic receptor antagonist mecamylamine, inhibitors of neuronal nitric oxide synthase (nNOS) and soluble guanylyl cyclase (sGC), and can be mimicked by the nitric oxide (NO) donor sodium nitroprusside.
      • Carbamylcholine increased NO metabolite content in the coronary effluent and this was prevented by mecamylamine.
      • The anti-fibrillatory action of both carbamylcholine and sodium nitroprusside was ultimately dependent on muscarinic receptor stimulation as all effects were blocked by atropine.
      • These data demonstrate a protective effect of carbamylcholine on VFT that depends upon both muscarinic and nicotinic receptor stimulation, where the generation of NO is likely to be via a neuronal nNOS–sGC dependent pathway.
    2. Endolysosomal two-pore channels regulate autophagy in cardiomyocytes

      Vanessa García-Rúa, Sandra Feijóo-Bandín, Diego Rodríguez-Penas, Ana Mosquera-Leal, Emad Abu-Assi, Andrés Beiras, Luisa María Seoane, Pamela Lear, John Parrington, Manuel Portolés, Esther Roselló-Lletí, Miguel Rivera, Oreste Gualillo, Valentina Parra, Joseph A. Hill, Beverly Rothermel, José Ramón González-Juanatey and Francisca Lago

      Article first published online: 4 FEB 2016 | DOI: 10.1113/JP271332

      Key points

      • Two-pore channels (TPCs) were identified as a novel family of endolysosome-targeted calcium release channels gated by nicotinic acid adenine dinucleotide phosphate, as also as intracellular Na+ channels able to control endolysosomal fusion, a key process in autophagic flux.
      • Autophagy, an evolutionarily ancient response to cellular stress, has been implicated in the pathogenesis of a wide range of cardiovascular pathologies, including heart failure.
      • We report direct evidence indicating that TPCs are involved in regulating autophagy in cardiomyocytes, and that TPC knockout mice show alterations in the cardiac lysosomal system. TPC downregulation implies a decrease in the viability of cardiomyocytes under starvation conditions. In cardiac tissues from both humans and rats, TPC transcripts and protein levels were higher in females than in males, and correlated negatively with markers of autophagy.
      • We conclude that the endolysosomal channels TPC1 and TPC2 are essential for appropriate basal and induced autophagic flux in cardiomyocytes, and also that they are differentially expressed in male and female hearts.
  11. Corrigendum

    1. You have free access to this content
      Corrigendum

      Article first published online: 4 FEB 2016 | DOI: 10.1113/JP272133

      This article corrects:

      Deranged sodium to sudden death

      Vol. 593, Issue 6, 1331–1345, Article first published online: 13 MAR 2015

  12. CrossTalk

    1. You have free access to this content
      Rebuttal from Raj K Goyal

      Raj K Goyal

      Article first published online: 3 FEB 2016 | DOI: 10.1113/JP271972

  13. Crosstalk

    1. You have free access to this content
  14. CrossTalk

    1. You have free access to this content
      Rebuttal from Kenton M. Sanders, Sean M. Ward and Andreas Friebe

      Kenton M. Sanders, Sean M. Ward and Andreas Friebe

      Article first published online: 3 FEB 2016 | DOI: 10.1113/JP271971

    2. You have free access to this content
      Interstitial cells are involved and physiologically important in neuromuscular transmission in the gut

      Kenton M. Sanders, Sean M. Ward and Andreas Friebe

      Article first published online: 3 FEB 2016 | DOI: 10.1113/JP271600

  15. Integrative

    1. Assessment of in vivo fetal growth and placental vascular function in a novel intrauterine growth restriction model of progressive uterine artery occlusion in guinea pigs

      Emilio A. Herrera, René Alegría, Marcelo Farias, Farah Díaz-López, Cherie Hernández, Ricardo Uauy, Timothy R. H. Regnault, Paola Casanello and Bernardo J. Krause

      Article first published online: 2 FEB 2016 | DOI: 10.1113/JP271467

      Key points

      • Intrauterine growth restriction (IUGR) is associated with short- and long-term detrimental cardiometabolic effects.
      • Mice and rats are commonly used to assess IUGR, but differences in placental and fetal developmental physiology relative to those in humans highlight the need for alternative small animal IUGR models.
      • We developed a guinea pig IUGR model by gradual occlusion of uterine arteries by ameroid constrictor implantation. In this model, reduced uterine blood flow was associated with IUGR, allowing in vivo assessment of fetal growth trajectory and umbilico-placental vascular function in conscious animals.
      • The intervention induces placental vascular dysfunction and remodelling, as well as altered fetal abdominal growth resulting in an asymmetric IUGR and preserved brain growth.
  16. Cardiovascular

    1. Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII-constitutive phosphorylation of RyR2 at site S2814

      G. Mazzocchi, L. Sommese, J. Palomeque, J. I. Felice, M. N. Di Carlo, D. Fainstein, P. Gonzalez, P. Contreras, D. Skapura, M. D. McCauley, E. C. Lascano, J. A. Negroni, E. G. Kranias, X. H. T. Wehrens, C. A. Valverde and A. Mattiazzi

      Article first published online: 2 FEB 2016 | DOI: 10.1113/JP271622

      Key points

      • Mice with Ca2+–calmodulin-dependent protein kinase (CaMKII) constitutive pseudo-phosphorylation of the ryanodine receptor RyR2 at Ser2814 (S2814D+/+ mice) exhibit a higher open probability of RyR2, higher sarcoplasmic reticulum (SR) Ca2+ leak in diastole and increased propensity to arrhythmias under stress conditions.
      • We generated phospholamban (PLN)-deficient S2814D+/+ knock-in mice by crossing two colonies, S2814D+/+ and PLNKO mice, to test the hypothesis that PLN ablation can prevent the propensity to arrhythmias of S2814D+/+ mice.
      • PLN ablation partially rescues the altered intracellular Ca2+ dynamics of S2814D+/+ hearts and myocytes, but enhances SR Ca2+ sparks and leak on confocal microscopy.
      • PLN ablation diminishes ventricular arrhythmias promoted by CaMKII phosphorylation of S2814 on RyR2.
      • PLN ablation aborts the arrhythmogenic SR Ca2+ waves of S2814D+/+ and transforms them into non-propagating events.
      • A mathematical human myocyte model replicates these results and predicts the increase in SR Ca2+ uptake required to prevent the arrhythmias induced by a CaMKII-dependent leaky RyR2.
  17. Neuroscience – cellular/molecular

    1. Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism

      Patricia M. G. E. Brown, Mark R. P. Aurousseau, Maria Musgaard, Philip C. Biggin and Derek Bowie

      Article first published online: 2 FEB 2016 | DOI: 10.1113/JP271690

      Key points

      • Kainate receptor heteromerization and auxiliary subunits, Neto1 and Neto2, attenuate polyamine ion-channel block by facilitating blocker permeation.
      • Relief of polyamine block in GluK2/GluK5 heteromers results from a key proline residue that produces architectural changes in the channel pore α-helical region.
      • Auxiliary subunits exert an additive effect to heteromerization, and thus relief of polyamine block is due to a different mechanism.
      • Our findings have broad implications for work on polyamine block of other cation-selective ion channels.
  18. Molecular and cellular

    1. Pore dilatation increases the bicarbonate permeability of CFTR, ANO1 and glycine receptor anion channels

      Ikhyun Jun, Mary Hongying Cheng, Eunji Sim, Jinsei Jung, Bong Lim Suh, Yonjung Kim, Hankil Son, Kyungsoo Park, Chul Hoon Kim, Joo-Heon Yoon, David C. Whitcomb, Ivet Bahar and Min Goo Lee

      Article first published online: 2 FEB 2016 | DOI: 10.1113/JP271311

      Key points

      • Cellular stimuli can modulate the ion selectivity of some anion channels, such as CFTR, ANO1 and the glycine receptor (GlyR), by changing pore size.
      • Ion selectivity of CFTR, ANO1 and GlyR is critically affected by the electric permittivity and diameter of the channel pore.
      • Pore size change affects the energy barriers of ion dehydration as well as that of size-exclusion of anion permeation.
      • Pore dilatation increases the bicarbonate permeability (inline image) of CFTR, ANO1 and GlyR.
      • Dynamic change in inline image may mediate many physiological and pathological processes.
  19. Cardiovascular

    1. Predicting the risk of sudden cardiac death

      Claudia Lerma and Leon Glass

      Article first published online: 2 FEB 2016 | DOI: 10.1113/JP270535

      Thumbnail image of graphical abstract

      Schematic diagram showing sudden cardiac death as a transition from sinus rhythm to ventricular tachycardia (VT) or ventricular fibrillation (VF). The onset of VT or VF is preceded by premature ventricular complex (PVC), which could originate by any of these mechanisms: reentry, spontaneous pacemaker or triggered activity. The ECG trace was taken from the Sudden Cardiac Death Database (record number 32) from www.physionet.org.

    2. Therapy for ventricular arrhythmias in structural heart disease: a multifaceted challenge

      Riccardo Proietti, Jacqueline Joza and Vidal Essebag

      Article first published online: 27 JAN 2016 | DOI: 10.1113/JP270534

      Thumbnail image of graphical abstract

      The flowchart shows clinical pathways for prevention of sudden cardiac death in patients with structural heart disease. Blue boxes and arrows show current clinical practice. Green boxes and arrows describe potential future directions. *Cardiac magnetic resonance imaging, T wave alternans, high-resolution voltage substrate mapping, electrophysiological evaluation of anatomical and functional components of potential arrhythmia circuits and patterns of VT initiation.

  20. Molecular and cellular

    1. TRPM7 kinase activity regulates murine mast cell degranulation

      Susanna Zierler, Adriana Sumoza-Toledo, Sayuri Suzuki, Fionán Ó Dúill, Lillia V. Ryazanova, Reinhold Penner, Alexey G. Ryazanov and Andrea Fleig

      Article first published online: 27 JAN 2016 | DOI: 10.1113/JP271564

      Key points

      • The Mg2+ and Ca2+ conducting transient receptor potential melastatin 7 (TRPM7) channel–enzyme (chanzyme) has been implicated in immune cell function.
      • Mice heterozygous for a TRPM7 kinase deletion are hyperallergic, while mice with a single point mutation at amino acid 1648, silencing kinase activity, are not.
      • As mast cell mediators trigger allergic reactions, we here determine the function of TRPM7 in mast cell degranulation and histamine release.
      • Our data establish that TRPM7 kinase activity regulates mast cell degranulation and release of histamine independently of TRPM7 channel function.
      • Our findings suggest a regulatory role of TRPM7 kinase activity on intracellular Ca2+ and extracellular Mg2+ sensitivity of mast cell degranulation.
  21. Neuroscience - cellular/molecular

    1. Stem cell-derived astrocytes: are they physiologically credible?

      Eric Hill, David Nagel, Rheinallt Parri and Michael Coleman

      Article first published online: 23 JAN 2016 | DOI: 10.1113/JP270658

      Thumbnail image of graphical abstract

      Astrocytic cells have been derived from a variety of stem cell sources. This review discusses the roles of astrocytes in the brain and highlights the extent to which human stem cell-derived astrocytes have demonstrated functional activities that are equivalent to those observed in vivo.

    2. Signalling beyond photon absorption: extracellular retinoids and growth factors modulate rod photoreceptor sensitivity

      Alex S. McKeown, Priyamvada M. Pitale and Timothy W. Kraft

      Article first published online: 23 JAN 2016 | DOI: 10.1113/JP271650

      Key points

      • We propose that the end product of chromophore bleaching in rod photoreceptors, all-trans retinol, is part of a feedback loop that increases the sensitivity of the phototransduction cascade in rods.
      • A previously described light-induced hypersensitivity in rods, termed adaptive potentiation, is reduced by exogenously applied all-trans retinol but not all-trans retinal.
      • This potentiation is produced by insulin-like growth factor-1, whose binding proteins are located in the extracellular matrix, even in our isolated retina preparation after removal of the retinal pigmented epithelium.
      • Simple modelling suggests that the light stimuli used in the present study will produce sufficient all-trans retinol within the interphotoreceptor matrix to explain the potentiation effect.
  22. Renal and endocrine

    1. Endothelin regulates intermittent hypoxia-induced lipolytic remodelling of adipose tissue and phosphorylation of hormone-sensitive lipase

      Anne Briançon-Marjollet, Denis Monneret, Marion Henri, Florence Hazane-Puch, Jean-Louis Pepin, Patrice Faure and Diane Godin-Ribuot

      Article first published online: 20 JAN 2016 | DOI: 10.1113/JP271321

      Key points

      • Endothelin-1 (ET-1) is upregulated upon intermittent hypoxia and has lipolytic effects.
      • Intermittent hypoxia induces adipose tissue lipolysis that may be mediated by ET-1.
      • In the present study, we show that ET-1 is involved in adipose tissue remodelling induced by intermittent hypoxia and that phosphorylation of hormone-sensitive lipase could be one mechanism mediating this effect.
      • We also show that ET-1 upregulates its own and its type A endothelin receptor expression, possibly leading to an autoactivatory loop.
      • These results help us better understand the mechanisms of dyslipidaemia in disorders associated with intermittent hypoxia, such as obstructive sleep apnoea.
  23. Neuroscience - behavioural/systems/cognitive

    1. The sensory origins of human position sense

      A. J. Tsay, M. J. Giummarra, T. J. Allen and U. Proske

      Article first published online: 19 JAN 2016 | DOI: 10.1113/JP271498

      Key points

      • Position sense at the human forearm can be measured in blindfolded subjects by matching positions of the arms or by a subject pointing to the perceived position of an unseen arm.
      • Effects on position sense tested were: elbow muscle conditioning with a voluntary contraction, muscle vibration, loading the arm and elbow skin stretch.
      • Conditioning contractions and vibration produced errors in a matching task, consistent with the action of muscle spindles as position sensors. Position errors in a pointing task were not consistent with the action of muscle spindles. Loading the arm or skin stretch had no effect in either matching or pointing tasks.
      • It is proposed that there are two kinds of position sense: (i) indicating positions of different body parts relative to one another, using signals from muscle spindles; and (ii) indicating position of the body in extrapersonal space, using signals from exteroceptors, vision, touch and hearing.
  24. Integrative

    1. Human placental renin–angiotensin system in normotensive and pre-eclamptic pregnancies at high altitude and after acute hypoxia–reoxygenation insult

      Lesia O. Kurlak, Hiten D. Mistry, Tereza Cindrova-Davies, Graham J. Burton and Fiona Broughton Pipkin

      Article first published online: 19 JAN 2016 | DOI: 10.1113/JP271045

      Key points

      • The development of the human placenta occurs in a low oxygen environment which stimulates angiogenesis and vascularization.
      • Placental expression of the renin angiotensin system (RAS) is highest in early pregnancy. Although both the RAS and oxygen stimulate angiogenesis, it is not known how they interact during placental development.
      • Pre-eclampsia (PE), a condition characterized by poor placental development and elevated oxidative stress has increased incidence in populations living at high altitude and thus exposed to hypobaric hypoxia.
      • This study aimed to investigate the effects of various forms of oxidative stress on the placental RAS.
      • The results suggest that the placental RAS is activated by oxidative insults but the component type and the degree of activation is dependent on the nature of the insult.
  25. Alimentary

    1. You have full text access to this OnlineOpen article
      Ageing and gastrointestinal sensory function: altered colonic mechanosensory and chemosensory function in the aged mouse

      Christopher Keating, Linda Nocchi, Yang Yu, Jemma Donovan and David Grundy

      Article first published online: 19 JAN 2016 | DOI: 10.1113/JP271403

      Key points

      • Remarkably little is known about how age affects the sensory signalling pathways in the gastrointestinal tract despite age-related gastrointestinal dysfunction being a prime cause of morbidity amongst the elderly population
      • High-threshold gastrointestinal sensory nerves play a key role in signalling distressing information from the gut to the brain.
      • We found that ageing is associated with attenuated high-threshold afferent mechanosensitivity in the murine colon, and associated loss of TRPV1 channel function.
      • These units have the capacity to sensitise in response to injurious events, and their loss in ageing may predispose the elderly to lower awareness of GI injury or disease.
  26. Cardiovascular

    1. Electrical effects of stem cell transplantation for ischaemic cardiomyopathy: friend or foe?

      Seth Mount and Darryl R. Davis

      Article first published online: 19 JAN 2016 | DOI: 10.1113/JP270540

      Thumbnail image of graphical abstract

      Potential effects of stem cell transplantation on electrical remodeling after myocardial infarction.

    2. You have full text access to this OnlineOpen article
      Mechanistically based mapping of human cardiac fibrillation

      Sanjiv M. Narayan and Junaid A. B. Zaman

      Article first published online: 19 JAN 2016 | DOI: 10.1113/JP270513

      Thumbnail image of graphical abstract

      Hierarchical and non-hierarchical mechanisms for cardiac fibrillation. Cardiac fibrillation is characterized by disorganized activation and recovery both spatially and temporally. The central dichotomy is whether this disorder is sustained by preferred regional sources (hierarchical model), illustrated by a central driving rotor that replenishes surrounding fibrillatory waves, or self-sustains (non-hierarchical model), illustrated by transient wavelets. These mechanisms can also be divided by the type of mapping. Cardiac chambers depicted are right and left atria. (Modified from Calkins et al. 2012.)

    3. The pioneering work of George Mines on cardiac arrhythmias: groundbreaking ideas that remain influential in contemporary cardiac electrophysiology

      Martin Aguilar and Stanley Nattel

      Article first published online: 19 JAN 2016 | DOI: 10.1113/JP270506

      Thumbnail image of graphical abstract

      Mine's major contribution to the field of cardiac electrophysiology was the notion of circus movement reentry, a concept with far-reaching theoretical and clinical applications that remains highly relevant in modern electrophysiology. His model of cardiac fibrillation based on circus movement reentry paved the way for modern theories of fibrillation such as leading circle and spiral wave reentry. Mines was also instrumental in developing the notion of the vulnerable period of the cardiac cycle, the time window during which an extra-stimulus can trigger fibrillation, which forms the basis of several practical applications (e.g., synchronized cardioversion and pacemaker sensing function). Other noteworthy contributions include the description of the effects of metabolic abnormalities and vagal nerve stimulation on the electrocardiogram. Presently-used practical clinical applications resulting from Mines' discoveries are shown in the grey boxes.

    4. The role of oxysterols in vascular ageing

      Simona Gargiulo, Paola Gamba, Gabriella Testa, Gabriella Leonarduzzi and Giuseppe Poli

      Article first published online: 19 JAN 2016 | DOI: 10.1113/JP271168

      Thumbnail image of graphical abstract

      Oxysterol-driven anticipation and/or amplification of the main features of ageing blood vessels.

  27. Integrative

    1. Symmorphosis and skeletal muscle V̇O2 max : in vivo and in vitro measures reveal differing constraints in the exercise-trained and untrained human

      Jayson R. Gifford, Ryan S. Garten, Ashley D. Nelson, Joel D. Trinity, Gwenael Layec, Melissa AH Witman, Joshua C. Weavil, Tyler Mangum, Corey Hart, Cory Etheredge, Jake Jessop, Amber Bledsoe, David E. Morgan, D. Walter Wray, Matthew J. Rossman and Russell S. Richardson

      Article first published online: 19 JAN 2016 | DOI: 10.1113/JP271229

      Key points

      • The concept of symmorphosis predicts that the capacity of each step of the oxygen cascade is attuned to the task demanded of it during aerobic exercise at maximal rates of oxygen consumption (inline image) such that no single process is limiting or in excess at inline image.
      • The present study challenges the applicability of this concept to humans by revealing clear, albeit very different, limitations and excesses in oxygen supply and consumption among untrained and endurance-trained humans.
      • Among untrained individuals, inline image is limited by the capacity of the mitochondria to consume oxygen, despite an excess of oxygen supply, whereas, among trained individuals, inline image is limited by the supply of oxygen to the mitochondria, despite an excess of mitochondrial respiratory capacity.
  28. Computational physiology and modelling

    1. How computer simulations of the human heart can improve anti-arrhythmia therapy

      Natalia A. Trayanova and Kelly C. Chang

      Article first published online: 18 JAN 2016 | DOI: 10.1113/JP270532

      Thumbnail image of graphical abstract

      Block diagram for generation of models of individual hearts from late-gadolinium enhanced cardiac magnetic resonance images for electrophysiological simulation studies (modified with permission from Ukwatta et al. 2015).

  29. Neuroscience - cellular/molecular

    1. Neuromodulation of fast-spiking and non-fast-spiking hippocampal CA1 interneurons by human cerebrospinal fluid

      Andreas Bjorefeldt, Pontus Wasling, Henrik Zetterberg and Eric Hanse

      Article first published online: 18 JAN 2016 | DOI: 10.1113/JP271553

      Key points

      • How the brain extracellular fluid influences the activity of GABAergic interneurons in vivo is not known.
      • This issue is examined in the hippocampal brain slice by comparing GABAergic interneuron activity in human versus artificial cerebrospinal fluid.
      • Human cerebrospinal fluid (hCSF) substantially increases the excitability of fast-spiking and non-fast-spiking CA1 interneurons.
      • CA1 pyramidal cells are even more strongly excited by hCSF.
      • The tonic excitation of pyramidal cells, in combination with an increased responsiveness of interneurons to excitatory input, is likely to promote the generation of synchronized network activity in the hippocampus.
  30. Cardiovascular

    1. Rigid and remodelled: cerebrovascular structure and function after experimental high-thoracic spinal cord transection

      A. A. Phillips, N. Matin, B. Frias, M. M. Z. Zheng, M. Jia, C. West, A. M. Dorrance, I. Laher and A. V. Krassioukov

      Article first published online: 18 JAN 2016 | DOI: 10.1113/JP270925

      Key points

      • Spinal cord injury (SCI) is associated with a 3–4 fold increased risk of stroke, and impaired cerebral blood flow regulation, although the effect of SCI on the structure and function of the cerebral arteries is unclear.
      • Using pressure myography to assess isolated vessels distended at physiological pressures, we provide novel evidence that experimental SCI leads to inward cerebrovascular remodelling, increased stiffness and impaired reactivity of the largest cerebral artery.
      • Histochemical analyses revealed that a profibrotic environment within the largest cerebral artery occurs after SCI, which was characterized by greater collagen and less elastin. This may be due to increased transforming growth factor β, a well-known profibrotic signalling protein.
      • Further analysis revealed that profibrotic alterations were not due to disruption of descending sympathetic pathways to the cerebrovasculature.
      • Experimental SCI exerts a deleterious influence on the structure and function of cerebral arteries, which may underlie the increased risk of stroke and impaired cerebral blood flow regulation.
  31. Neuroscience - cellular/molecular

    1. Functional coupling of diverse voltage-gated Ca2+ channels underlies high fidelity of fast dendritic Ca2+ signals during burst firing

      Nadia Jaafari and Marco Canepari

      Article first published online: 18 JAN 2016 | DOI: 10.1113/JP271830

      Key points

      • In neurons, the Ca2+ signal associated with the dendritic back-propagating action potential codes a chemical message to the different dendritic sites, playing a crucial role in electrical signalling, synaptic transmission and synaptic plasticity.
      • The study of the underlying Ca2+ current, mediated by different types of voltage-gated Ca2+ channels, cannot be achieved by using the patch clamp technique.
      • In this article, we used a recently developed cutting-edge optical technique to investigate the physiological behaviour of local Ca2+ currents along the apical dendrite of CA1 hippocampal pyramidal neurons.
      • We directly measure, for the first time, the synergistic activation and deactivation of the diverse dendritic voltage-gated Ca2+ channels operating during bursts of back-propagating action potentials to precisely control the Ca2+ signal.
      • We demonstrate that the Ca2+ loss via high-voltage-activated channels is compensated by the Ca2+ entry via the other channels translating in high fidelity of Ca2+ signalling.
  32. Muscle

    1. Do antioxidant supplements interfere with skeletal muscle adaptation to exercise training?

      Troy L. Merry and Michael Ristow

      Article first published online: 18 JAN 2016 | DOI: 10.1113/JP270654

      Thumbnail image of graphical abstract

      Acute exercise increases the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which contribute to the signalling of skeletal muscle adaptations that occur with training. Preventing ROS/RNS stress during exercise through antioxidant supplementation could potentially impair the adaptation process. ROS/RNS are likely to exhibit a hormetic effect on skeletal muscle adaptations during exercise, with physiological increases promoting, and very low or very high exposure potentially hampering adaptation.

  33. Neuroscience - cellular/molecular

    1. Determinants of rebound burst responses in rat cerebellar nuclear neurons to physiological stimuli

      Steven Dykstra, Jordan D. T. Engbers, Theodore M. Bartoletti and Ray W. Turner

      Article first published online: 18 JAN 2016 | DOI: 10.1113/JP271894

      Key points

      • Cerebellar Purkinje cells project GABAergic inhibitory input to neurons of the deep cerebellar nuclei (DCN) that generate a rebound increase in firing, but the specific patterns of input that might elicit a rebound response have not been established.
      • We used recordings of Purkinje cell firing obtained during perioral whisker stimulation in vivo to create a physiological stimulus template to activate Purkinje cell afferents in vitro.
      • DCN cell bursts were evoked by the stimulus pattern but not in relation to the perioral whisker stimulus, complex spikes or regular patterns within the Purkinje cell record.
      • Reverse correlation revealed that bursts were triggered by an elevation-pause pattern of Purkinje cell firing, with pause duration a key factor in burst generation.
      • Our data identify for the first time a physiological pattern of Purkinje cell input that can be encoded by the generation of rebound bursts in DCN cells.
    2. Asynchronous presynaptic glutamate release enhances neuronal excitability during the post-spike refractory period

      Karl J. Iremonger and Jaideep S. Bains

      Article first published online: 18 JAN 2016 | DOI: 10.1113/JP271485

      Key Points

      • Many excitatory synapses in the brain release glutamate with both synchronous and asynchronous components.
      • Immediately following an action potential, neurons display a reduced excitability due to the post-spike afterhyperpolarization (AHP). This gives rise to a relative refractory period.
      • When an action potential is evoked by glutamate synaptic input possessing asynchronous release, the delayed glutamate release events act to depolarize the neuron during the AHP and overcome the relative refractory period.
      • These results demonstrate a new role for asynchronous release in regulating post-spike excitability and the relative refractory period in central neurons.
  34. Integrative

    1. Resveratrol partially prevents oxidative stress and metabolic dysfunction in pregnant rats fed a low protein diet and their offspring

      Claudia C Vega, Luis A Reyes-Castro, Guadalupe L Rodríguez-González, Claudia J Bautista, Magaly Vázquez-Martínez, Fernando Larrea, Germán A Chamorro-Cevallos, Peter W Nathanielsz and Elena Zambrano

      Article first published online: 18 JAN 2016 | DOI: 10.1113/JP271543

      Key points

      • Maternal protein restriction during pregnancy increases both maternal and offspring oxidative stress and leads to metabolic dysfunction.
      • Maternal low protein diet during pregnancy increases maternal and offspring corticosterone.
      • Resveratrol administration partially prevents both maternal and offspring adverse outcomes induced by maternal protein restriction during pregnancy.
  35. Cardiovascular

    1. Increased susceptibility of spontaneously hypertensive rats to ventricular tachyarrhythmias in early hypertension

      Thao P. Nguyen, Ali A. Sovari, Arash Pezhouman, Shankar Iyer, Hong Cao, Christopher Y. Ko, Aneesh Bapat, Nooshin Vahdani, Mostafa Ghanim, Michael C. Fishbein and Hrayr S. Karagueuzian

      Article first published online: 18 JAN 2016 | DOI: 10.1113/JP271318

      Key points

      • Hypertension is a risk factor for sudden cardiac death caused by ventricular tachycardia and fibrillation.
      • Whether hypertension in its early stage is associated with an increased risk of ventricular tachyarrhythmias is not known.
      • Based on experiments performed at the cellular and whole heart levels, we show that, even early in chronic hypertension, the hypertrophied and fibrotic ventricles of spontaneously hypertensive rats aged 5 to 6 months have already developed increased stress-induced arrhythmogenicity, and this increased susceptibility to ventricular arrhythmias is primarily a result of tissue remodelling rather than cellular electrophysiological changes.
      • Our findings highlight the need for early hypertension treatment to minimize myocardial fibrosis, ventricular hypertrophy, and arrhythmias.
    2. Predicting drug-induced QT prolongation and torsades de pointes

      Dan M. Roden

      Article first published online: 18 JAN 2016 | DOI: 10.1113/JP270526

      Thumbnail image of graphical abstract

      The chain of molecular and cellular events that culminate in drug-induced torsades de pointes. The first event (A) is drug block of the Kv11.1 (‘HERG’) channel, leading to decreased IKr; recent evidence has also suggested an increase in late sodium current may contribute. This in turn results in prolongation of action potentials and generation of triggered activity from early afterdepolarization(s) (B), QT interval prolongation (C), and torsades de pointes (D).

  36. Muscle

    1. Increasing taurine intake and taurine synthesis improves skeletal muscle function in the mdx mouse model for Duchenne muscular dystrophy

      Jessica R. Terrill, Gavin J. Pinniger, Jamie A. Graves, Miranda D. Grounds and Peter G. Arthur

      Article first published online: 18 JAN 2016 | DOI: 10.1113/JP271418

      Key points

      • Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease associated with increased inflammation, oxidative stress and myofibre necrosis.
      • Cysteine precursor antioxidants such as N-acetyl cysteine (NAC) and l-2-oxothiazolidine-4-carboxylate (OTC) reduce dystropathology in the mdx mouse model for DMD, and we propose this is via increased synthesis of the amino acid taurine.
      • We compared the capacity of OTC and taurine treatment to increase taurine content of mdx muscle, as well as effects on in vivo and ex vivo muscle function, inflammation and oxidative stress.
      • Both treatments increased taurine in muscles, and improved many aspects of muscle function and reduced inflammation. Taurine treatment also reduced protein thiol oxidation and was overall more effective, as OTC treatment reduced body and muscle weight, suggesting some adverse effects of this drug.
      • These data suggest that increasing dietary taurine is a better candidate for a therapeutic intervention for DMD.
  37. Molecular and cellular

    1. Factors regulating quiescent stem cells: insights from the intestine and other self-renewing tissues

      Camilla A. Richmond, Manasvi S. Shah, Diana L. Carlone and David T. Breault

      Article first published online: 18 JAN 2016 | DOI: 10.1113/JP271653

      Thumbnail image of graphical abstract

      Schematic illustration of the intestinal crypt showing the location of both rapidly cycling crypt base columnar intestinal stem cells (CBC-ISCs) (gold) and quiescent intestinal stem cells (qISCs) (dark blue). Multiple CBC-ISCs are located at the crypt base and are marked by Lgr5 expression. In contrast, most crypts have a limited number of qISCs, which are marked by expression of various genes (e.g. mTert, Bmi1, Sox9hi, Lrig1, Hopx and Dclk1). qISCs are typically located in the ‘+4’ or supra-Paneth cell position. Mechanisms employed by stem cell populations to maintain quiescence include factors involved in regulating cell cycle, protection from DNA damage, stress resistance and survival, developmental signalling pathways and post-transcriptional modulation.

  38. Molecular & Cellular

    1. Angiopoietin-like 4 promotes angiogenesis in the tendon and is increased in cyclically loaded tendon fibroblasts

      Rouhollah Mousavizadeh, Alex Scott, Alex Lu, Gholamreza S Ardekani, Hayedeh Behzad, Kirsten Lundgreen, Mazyar Ghaffari, Robert G McCormack and Vincent Duronio

      Article first published online: 18 JAN 2016 | DOI: 10.1113/JP271752

      Key points

      • Angiopoietin-like 4 (ANGPTL4) modulates tendon neovascularization.
      • Cyclic loading stimulates the activity of transforming growth factor-β and hypoxia-inducible factor 1α and thereby increases the expression and release of ANGPTL4 from human tendon cells.
      • Targeting ANGPTL4 and its regulatory pathways is a potential avenue for regulating tendon vascularization to improve tendon healing or adaptation.
  39. Neuroscience - behavioural/systems/cognitive

    1. How environment and self-motion combine in neural representations of space

      Talfan Evans, Andrej Bicanski, Daniel Bush and Neil Burgess

      Article first published online: 6 JAN 2016 | DOI: 10.1113/JP270666

      Thumbnail image of graphical abstract

      Spatial navigation is thought to rely on complementary information from environmental sensory cues and an internal path integration system. An estimate of one's location within an environment can be constructed purely from environmental sensory information, however in sensory-poor environments (e.g. in the dark or far from geometrical cues) this estimate can also be maintained by integrating self-motion information, a process known as path integration (red dashed line). Path integration tracks changes in both the angular and translational components of movement, but is subject to drift over time due to the accumulation of error. Head direction cells (HDCs) and grid cells (GCs) are thought to represent the neural bases of these components and are known to be anchored to environmental cues, correcting for drift (mountain and purple arrows). Information on the distance to the boundaries of an environment is provided by boundary vector cells (BVCs).

    2. Promoting brain health through exercise and diet in older adults: a physiological perspective

      Philippa A. Jackson, Vincent Pialoux, Dale Corbett, Lauren Drogos, Kirk I. Erickson, Gail A. Eskes and Marc J. Poulin

      Article first published online: 6 JAN 2016 | DOI: 10.1113/JP271270

      Thumbnail image of graphical abstract

      Age-related changes in brain physiology. Ageing is associated with a number of structural, vascular and neuromolecular changes in the brain which contribute to impaired cognitive function. Modifiable lifestyle factors including physical activity, cognitive activity and a Mediterranean-style diet may attenuate the progression of these changes and protect against cognitive decline.

  40. Cardiovascular

    1. Stochastic pacing reveals the propensity to cardiac action potential alternans and uncovers its underlying dynamics

      Yann Prudat, Roshni V. Madhvani, Marina Angelini, Nils P. Borgstom, Alan Garfinkel, Hrayr S. Karagueuzian, James N. Weiss, Enno de Lange, Riccardo Olcese and Jan P. Kucera

      Article first published online: 6 JAN 2016 | DOI: 10.1113/JP271573

      Key points

      • Beat-to-beat alternation (alternans) of the cardiac action potential duration is known to precipitate life-threatening arrhythmias and can be driven by the kinetics of voltage-gated membrane currents or by instabilities in intracellular calcium fluxes.
      • To prevent alternans and associated arrhythmias, suitable markers must be developed to quantify the susceptibility to alternans; previous theoretical studies showed that the eigenvalue of the alternating eigenmode represents an ideal marker of alternans.
      • Using rabbit ventricular myocytes, we show that this eigenvalue can be estimated in practice by pacing these cells at intervals varying stochastically.
      • We also show that stochastic pacing permits the estimation of further markers distinguishing between voltage-driven and calcium-driven alternans.
      • Our study opens the perspective to use stochastic pacing during clinical investigations and in patients with implanted pacing devices to determine the susceptibility to, and the type of alternans, which are both important to guide preventive or therapeutic measures.
  41. Molecular and cellular

    1. Dopamine modulation of transient receptor potential vanilloid type 1 (TRPV1) receptor in dorsal root ganglia neurons

      Saikat Chakraborty, Mario Rebecchi, Martin Kaczocha and Michelino Puopolo

      Article first published online: 6 JAN 2016 | DOI: 10.1113/JP271198

      Key points

      • Transient receptor potential vanilloid type 1 (TRPV1) receptors transduce noxious thermal stimuli and are responsible for the thermal hyperalgesia associated with inflammatory pain.
      • A large population of dorsal root ganglia (DRG) neurons, including the C low threshold mechanoreceptors (C-LTMRs), express tyrosine hydroxylase, and probably release dopamine.
      • We found that dopamine and SKF 81297 (an agonist at D1/D5 receptors), but not quinpirole (an agonist at D2 receptors), downregulate the activity of TRPV1 channels in DRG neurons.
      • The inhibitory effect of SKF 81297 on TRPV1 channels was strongly dependent on external calcium and preferentially linked to calcium–calmodulin-dependent protein kinase II (CaMKII).
      • We suggest that modulation of TRPV1 channels by dopamine in nociceptive neurons may represent a way for dopamine to modulate incoming noxious stimuli.
  42. Cardiovascular

    1. The fetal brain sparing response to hypoxia: physiological mechanisms

      Dino A. Giussani

      Article first published online: 6 JAN 2016 | DOI: 10.1113/JP271099

      Thumbnail image of graphical abstract

      The fetal brain sparing response to hypoxia. The fetal brain sparing response to acute hypoxia is triggered by a carotid chemoreflex which leads to bradycardia and an increase in peripheral vasoconstriction. The bradycardia is mediated by a dominant vagal influence on the fetal heart. The neurally triggered peripheral vasoconstriction is maintained by the release of constrictor hormones into the fetal circulation as well as a local vascular oxidant tone, determined by the interaction between NO and ROS, such as the superoxide anion (·O2).

  43. Neuroscience - behavioural/systems/cognitive

    1. Dynorphin inhibits basal forebrain cholinergic neurons by pre- and postsynaptic mechanisms

      L. L. Ferrari, L. J. Agostinelli, M. J. Krashes, B. B. Lowell, T. E. Scammell and E. Arrigoni

      Article first published online: 5 JAN 2016 | DOI: 10.1113/JP271657

      Key points

      • The basal forebrain is an important component of the ascending arousal system and may be a key site through which the orexin neurons promote arousal.
      • It has long been known that orexin-A and -B excite basal forebrain cholinergic neurons, but orexin-producing neurons also make the inhibitory peptide dynorphin.
      • Using whole-cell recordings in brain slices, we found that dynorphin-A directly inhibits basal forebrain cholinergic neurons via κ-opioid receptors, and decreases afferent excitatory synaptic input to these neurons.
      • While the effects of dynorphin-A and orexin-A desensitize over multiple applications, co-application of dynorphin-A and orexin-A produces a sustained response that reverses depending on the membrane potential of basal forebrain cholinergic neurons. At −40 mV the net effect of the co-application is inhibition by dynorphin-A, whereas at −70 mV the excitatory response to orexin-A prevails.
    2. Environmental boundaries as a mechanism for correcting and anchoring spatial maps

      Lisa M. Giocomo

      Article first published online: 5 JAN 2016 | DOI: 10.1113/JP270624

      Thumbnail image of graphical abstract

      Medial entorhinal cortex grid cells (center) depend, in part, on self-motion cues such as vestibular information, optic flow and proprioceptive cues (left). The role of other primary sensory cues in modulated grid cell response properties remains to be fully elucidated (right).

  44. Neuroscience - development/plasticity/repair

    1. The consequences of fetal growth restriction on brain structure and neurodevelopmental outcome

      Suzanne L. Miller, Petra S. Huppi and Carina Mallard

      Article first published online: 5 JAN 2016 | DOI: 10.1113/JP271402

      Thumbnail image of graphical abstract

      The structural and functional deficits that are associated with fetal growth restriction in human infants are dependent on a number of important factors, including the timing of the onset of placental insufficiency and subsequent fetal hypoxia and hypoglycaemia, the severity of fetal compromise, whether the FGR infant is born preterm or at term, whether coexisting complications are present, and the cerebrovascular responses including whether brain sparing is evident and the severity of brain sparing, as well as the spatial redistribution of brain blood flow.

  45. Molecular and cellular

    1. You have full text access to this OnlineOpen article
      Calorie restriction as an intervention in ageing

      Guillermo López-Lluch and Plácido Navas

      Article first published online: 3 JAN 2016 | DOI: 10.1113/JP270543

      Thumbnail image of graphical abstract

      Calorie restriction modifies several essential pathways in the organisms. Molecular components of this response act by modifying physiological processes such as proliferation, inflammation, mitochondrial physiology and remodelling, autophagy and the expression of antioxidants. In general CR inhibits processes involved in cell proliferation and glycolysis through blocking IGF-I receptor-dependent pathways and Target of Rapamycin (TOR). At the same time, CR induces mitochondrial activity by activating AMP-dependent kinase (AMPK) and sirtuins. This effect is accompanied by a higher activity of Forkhead box proteins (FoxO) that activate both auto/mitophagy and antioxidant expression. Interestingly, this FoxO activation can be induced by both, TOR inhibition and AMPK activation. Nuclear factor erythroid 2-related factor 2 (NRF2) is also activated by CR and, by this mechanism, the expression of antioxidant proteins is induced. Finally, CR also inhibits Nuclear Factor-kB activity and reduces the proinflammatory profile found during ageing. Any of these processes contribute individually in the increase in healthspan and longevity found after CR.

  46. Neuroscience - cellular/molecular

    1. You have full text access to this OnlineOpen article
      Functional properties of in vitro excitatory cortical neurons derived from human pluripotent stem cells

      Matthew R. Livesey, Dario Magnani, Giles E. Hardingham, Siddharthan Chandran and David J. A. Wyllie

      Article first published online: 30 DEC 2015 | DOI: 10.1113/JP270660

      Thumbnail image of graphical abstract

      Many protocols now exist to derive excitatory cortical neurons from human pluripotent stem cells however the physiological properties of the neurons remain under explored.

  47. Neuroscience - behavioural/systems/cognitive

    1. You have full text access to this OnlineOpen article
      Effect of head pitch and roll orientations on magnetically induced vertigo

      Omar S. Mian, Yan Li, Andre Antunes, Paul M. Glover and Brian L. Day

      Article first published online: 30 DEC 2015 | DOI: 10.1113/JP271513

      Key points

      • Lying supine in a strong magnetic field, such as in magnetic resonance imaging scanners, can induce a perception of whole-body rotation.
      • The leading hypothesis to explain this invokes a Lorentz force mechanism acting on vestibular endolymph that acts to stimulate semicircular canals.
      • The hypothesis predicts that the perception of whole-body rotation will depend on head orientation in the field.
      • Results showed that the direction and magnitude of apparent whole-body rotation while stationary in a 7 T magnetic field is influenced by head orientation.
      • The data are compatible with the Lorentz force hypothesis of magnetic vestibular stimulation and furthermore demonstrate the operation of a spatial transformation process from head-referenced vestibular signals to Earth-referenced body motion.
  48. Neuroscience - cellular/molecular

    1. Mechanisms of 5-HT1A receptor-mediated transmission in dorsal raphe serotonin neurons

      Nicholas A. Courtney and Christopher P. Ford

      Article first published online: 30 DEC 2015 | DOI: 10.1113/JP271716

      Key points

      • In the dorsal raphe nucleus, it is known that serotonin release activates metabotropic 5-HT1A autoreceptors located on serotonin neurons that leads to an inhibition of firing through the activation of G-protein-coupled inwardly rectifying potassium channels.
      • We found that in mouse brain slices evoked serotonin release produced a 5-HT1A receptor-mediated inhibitory postsynaptic current (IPSC) that resulted in only a transient pause in firing.
      • While spillover activation of receptors contributed to evoked IPSCs, serotonin reuptake transporters prevented pooling of serotonin in the extrasynaptic space from activating 5-HT1A-IPSCs.
      • As a result, the decay of 5-HT1A-IPSCs was independent of the intensity of stimulation or the probability of transmitter release.
      • These results indicate that evoked serotonin transmission in the dorsal raphe nucleus mediated by metabotropic 5-HT1A autoreceptors may occur via point-to-point synapses rather than by paracrine mechanisms.
    2. Functionally heterogeneous synaptic vesicle pools support diverse synaptic signalling

      Simon Chamberland and Katalin Tóth

      Article first published online: 28 DEC 2015 | DOI: 10.1113/JP270194

      Thumbnail image of graphical abstract

      Single presynaptic terminals transmit information via functionally distinct modes of neurotransmitter release. Functional heterogeneity in the presynaptic terminal is largely supported by the existence of distinct pools of vesicles expressing unique sets of vesicle membrane proteins. These distinct pools can be generated via different modes of vesicle recycling pathways.

    3. The zebrafish pinball wizard gene encodes WRB, a tail-anchored-protein receptor essential for inner-ear hair cells and retinal photoreceptors

      Shuh-Yow Lin, Melissa A. Vollrath, Sara Mangosing, Jun Shen, Elena Cardenas and David P. Corey

      Article first published online: 28 DEC 2015 | DOI: 10.1113/JP271437

      Key points

      • The zebrafish pinball wizard (pwi) mutant is deaf and blind.
      • The pwi phenotype includes a reduced auditory startle response and reduced visual evoked potentials, suggesting fatigue of synaptic release at ribbon synapses in hair cells and photoreceptors.
      • The gene defective in the pwi mutant is WRB, a protein homologous to the yeast protein Get1, which is involved in the insertion of ‘tail-anchored’ membrane proteins.
      • Many tail-anchored proteins are associated with synaptic vesicles, and both vesicles and synaptic ribbons are reduced in synaptic regions of hair cells in pwi.
      • Abnormal processing of synaptic vesicle proteins important for ribbon synapses can explain the pwi phenotype.
  49. Renal and endocrine

    1. Unilateral renal ischaemia in rats induces a rapid secretion of inflammatory markers to renal lymph and increased capillary permeability

      Liliana Monica Bivol, the late Bjarne Magnus Iversen, Michael Hultström, Paal William Wallace, Rolf Kåre Reed, Helge Wiig and Olav Tenstad

      Article first published online: 28 DEC 2015 | DOI: 10.1113/JP271578

      Key points

      • Transient reduction in renal blood flow results in inflammation and is a primary cause of acute kidney injury, thereby representing a major clinical problem.
      • It is not known whether the inflammatory reaction is local only or part of a systemic response.
      • We accessed the renal microenvironment through isolation of lymph and were in this way able to investigate whether the inflammatory reaction is local or systemic.
      • Transient ischaemia followed by reperfusion resulted in a rapid production of inflammatory mediators locally in the renal interstitium.
      • We moreover showed that the injury response affected the glomerular as well as the non-glomerular barrier and resulted in a reduced size and charge selectivity of the glomerular capillaries.
  50. Molecular and cellular

    1. Structural and molecular regulation of lung maturation by intratracheal vascular endothelial growth factor administration in the normally grown and placentally restricted fetus

      Erin V. McGillick, Sandra Orgeig and Janna L Morrison

      Article first published online: 23 DEC 2015 | DOI: 10.1113/JP271113

      Key points

      • Ablation of hypoxia signalling leads to respiratory distress syndrome (RDS). Administering vascular endothelial growth factor (VEGF) protects from RDS.
      • Reduced surfactant maturation in the chronically hypoxaemic placentally restricted (PR) fetus is associated with altered regulation of hypoxia signalling and may predispose to RDS.
      • We determined the effect of intratracheal VEGF administration on the expression of genes regulating vascularization, alveolarization, proliferation, inflammation, surfactant maturation and structural markers of lung maturation in the normally grown and PR fetus.
      • Although there were relatively few effects of VEGF on gene expression, there were positive effects on structural maturation in the normally grown and PR lung. There was no effect on fetal blood pressure or fetal breathing movements.
      • We have provided evidence that VEGF promotes structural fetal lung maturation and may result in synergistic effects if combined with current therapeutic treatments aiming to induce surfactant maturation and reduce the risk of RDS.
    2. Adaptive responses of cell hydration to a low temperature arrest

      Jens Christmann, Lale Azer, Daniel Dörr, Günter R. Fuhr, Philippe I. H. Bastiaens and Frank Wehner

      Article first published online: 22 DEC 2015 | DOI: 10.1113/JP271245

      Key points

      • Na+ conducting cation channels are key players in the volume restoration of osmotically shrunken cells. Accordingly, they are potential candidates for the compensation of water loss during slow-freezing procedures.
      • Cells were subjected to different levels of hypertonic stress, aiming to disturb cell water content and to define the energy demands of water channels and Na+ channels in the process of rehydration.
      • Activation of Na+ channels was clearly the rate-limiting step in the restoration of cell volume post-cryo, whereas water channels merely played a permissive role.
      • Low temperatures increased cell viscosity with a remarkable hysteresis; furthermore, increasing cell viscosity experimentally was shown to stimulate Na+ channels.
      • The peptide hormone vasopressin was a further activator of Na+ channels and increased the viability of post-cryo cells considerably. This opens the path for a new class of cryo-protectants with an intrinsic biological activity.
  51. Cardiovascular

    1. Compromised blood–brain barrier permeability: novel mechanism by which circulating angiotensin II signals to sympathoexcitatory centres during hypertension

      V. C. Biancardi and J. E. Stern

      Article first published online: 21 DEC 2015 | DOI: 10.1113/JP271584

      Thumbnail image of graphical abstract

      Proposed model of circulating angiotensin II (AngII) signalling pathways in the brain under normotensive and hypertensive conditions. Under normal conditions (left, blue), and due to its hydrophilic nature, circulating AngII does not cross the blood–brain barrier (BBB) and signals to the brain through the circumventricular organs (mainly the SFO), which lack a tight BBB. The SFO then engages the PVN–RVLM–IML pathway, increasing sympathetic nerve activity to the circulation. During hypertension (right, red), circulating AngII leads to BBB breakdown, allowing its own leakage into the PVN and RVLM parenchyma, resulting in overactivation of the PVN–RVLM–IML pathway and exacerbated sympathoexcitatory outflow to the circulation. BP, blood pressure; IML, intermediolateral cell column; LT, lamina terminalis; MnPO, median preoptic nucleus; OVLT, organum vasculosum of the lamina terminalis; PVN, paraventricular nucleus; RVLM, rostral ventrolateral medulla; SFO, subfornical organ; SNA, sympathetic nerve activity; SON, supraoptic nucleus.

  52. Neuroscience - cellular/molecular

    1. Noradrenaline goes nuclear: epigenetic modifications during long-lasting synaptic potentiation triggered by activation of β-adrenergic receptors

      Sabyasachi Maity, Timothy J. Jarome, Jessica Blair, Farah D. Lubin and Peter V. Nguyen

      Article first published online: 21 DEC 2015 | DOI: 10.1113/JP271432

      Key points

      • Transcription is recruited by noradrenaline in the hippocampus.
      • Epigenetic mechanisms are recruited by hippocampal noradrenergic receptor activation.
      • Epigenetic regulation by noradrenaline offers a novel mechanism for long-term potentiation
  53. Muscle

    1. Innervation and neuromuscular control in ageing skeletal muscle

      Russell T. Hepple and Charles L. Rice

      Article first published online: 21 DEC 2015 | DOI: 10.1113/JP270561

      Thumbnail image of graphical abstract

      Schematic depiction of the aging motor unit where fibers of the same colour belong to the same motor unit. A degenerating axon is depicted by the dashed orange line.

  54. Integrative

    1. Redox interventions to increase exercise performance

      Michael B. Reid

      Article first published online: 20 DEC 2015 | DOI: 10.1113/JP270653

      Thumbnail image of graphical abstract

      Antioxidants, dietary nitrates and exercise performance. Continuous lines: biological actions that are promoted (positive symbol, arrowhead) or opposed (negative symbol, blunt end) by endogenous reactive oxygen species (ROS) and NO derivatives during exercise. Dashed lines: actions by which exogenous antioxidants and dietary nitrate may improve (positive symbol, arrow) or depress (negative symbol, blunt end) exercise performance. NAC, N-acetylcysteine; SOD, superoxide dismutase.

  55. Cardiovascular

    1. Heterogeneous ageing of skeletal muscle microvascular function

      Judy M. Muller-Delp

      Article first published online: 20 DEC 2015 | DOI: 10.1113/JP271005

      Thumbnail image of graphical abstract

      In the skeletal muscle resistance vasculature, muscle-specific signals from nerves, muscle metabolites, intraluminal flow and transmural pressure change with age and declining activity. Resulting vascular adaptations in the endothelium include changes in signalling through nitric oxide, prostanoids and reactive oxygen species. In the vascular smooth muscle, age induces hyperplasia, reduced expression of contractile proteins and alterations in receptor expression. These changes in both the endothelium and the vascular smooth muscle are muscle and fibre type specific.

  56. Molecular and cellular

    1. You have full text access to this OnlineOpen article
      Hypercapnia modulates cAMP signalling and cystic fibrosis transmembrane conductance regulator-dependent anion and fluid secretion in airway epithelia

      Mark J. Turner, Vinciane Saint-Criq, Waseema Patel, Salam H. Ibrahim, Bernard Verdon, Christopher Ward, James P. Garnett, Robert Tarran, Martin J. Cann and Michael A. Gray

      Article first published online: 20 DEC 2015 | DOI: 10.1113/JP271309

      Key points

      • Raised arterial blood CO2 (hypercapnia) is a feature of many lung diseases.
      • CO2 has been shown to act as a cell signalling molecule in human cells, notably by influencing the levels of cell signalling second messengers: cAMP and Ca2+.
      • Hypercapnia reduced cAMP-stimulated cystic fibrosis transmembrane conductance regulator-dependent anion and fluid transport in Calu-3 cells and primary human airway epithelia but did not affect cAMP-regulated HCO3 transport via pendrin or Na+/HCO3 cotransporters.
      • These results further support the role of CO2 as a cell signalling molecule and suggests CO2-induced reductions in airway anion and fluid transport may impair innate defence mechanisms of the lungs.
  57. Neuroscience - cellular/molecular

    1. Differential signalling and glutamate receptor compositions in the OFF bipolar cell types in the mouse retina

      Tomomi Ichinose and Chase B. Hellmer

      Article first published online: 20 DEC 2015 | DOI: 10.1113/JP271458

      Key points

      • Using whole-cell clamp methods, we characterized the temporal coding in each type of OFF bipolar cell.
      • We found that type 2 and 3a cells are transient, type 1 and 4 cells are sustained, and type 3b cells are intermediate.
      • The light-evoked excitatory postsynaptic potentials in some types were rectified, suggesting that they provide inputs to the non-linear ganglion cells.
      • Visual signalling from the photoreceptors was mediated exclusively through the kainate receptors in the transient OFF bipolar cells, whereas both kainate and AMPA receptors contributed in the other cells.
      • This study demonstrates, for the first time, that parallel visual encoding starts at the OFF bipolar cells in a type-specific manner.
    2. You have full text access to this OnlineOpen article
      Synapse-specific expression of calcium-permeable AMPA receptors in neocortical layer 5

      Txomin Lalanne, Julia Oyrer, Adamo Mancino, Erica Gregor, Andrew Chung, Louis Huynh, Sasha Burwell, Jérôme Maheux, Mark Farrant and P. Jesper Sjöström

      Article first published online: 17 DEC 2015 | DOI: 10.1113/JP271394

      Key points

      • In the hippocampus, calcium-permeable AMPA receptors have been found in a restricted subset of neuronal types that inhibit other neurons, although their localization in the neocortex is less well understood.
      • In the present study, we looked for calcium-permeable AMPA receptors in two distinct populations of neocortical inhibitory neurons: basket cells and Martinotti cells. We found them in the former but not in the latter. Furthermore, in basket cells, these receptors were associated with particularly fast responses.
      • Computer modelling predicted (and experiments verified) that fast calcium-permeable AMPA receptors enable basket cells to respond rapidly, such that they promptly inhibit neighbouring cells and shut down activity.
      • The results obtained in the present study help our understanding of pathologies such as stroke and epilepsy that have been associated with disordered regulation of calcium-permeable AMPA receptors.
  58. Neuroscience - development/plasticity/repair

    1. You have full text access to this OnlineOpen article
      Age-related neuromuscular changes affecting human vastus lateralis

      M. Piasecki, A. Ireland, D. Stashuk, A. Hamilton-Wright, D. A. Jones and J. S. McPhee

      Article first published online: 15 DEC 2015 | DOI: 10.1113/JP271087

      Key points

      • Skeletal muscle size and strength decline in older age.
      • The vastus lateralis, a large thigh muscle, undergoes extensive neuromuscular remodelling in healthy ageing, as characterized by a loss of motor neurons, enlargement of surviving motor units and instability of neuromuscular junction transmission.
      • The loss of motor axons and changes to motor unit potential transmission precede a clinically-relevant loss of muscle mass and function.
  59. Molecular and cellular

    1. Calcium signalling in salivary gland physiology and dysfunction

      Indu S. Ambudkar

      Article first published online: 15 DEC 2015 | DOI: 10.1113/JP271143

      Thumbnail image of graphical abstract

      Ca2+ signalling in cells is a double-edged sword: the tool kit that is involved in maintaining and regulating normal cell function can also be involved in pathophysiology. Normal physiological stimuli induce cytosolic Ca2+ signals by regulating the Ca2+ signalling toolkit, which includes various Ca2+ flux pathways as well as Ca2+-regulated targets such as ion channels, enzymes and transcription factors. Under these conditions, Ca2+ homeostasis is maintained and cells display physiological responses. However, pathophysiological stimuli often generate unregulated and aberrant Ca2+ signals in cells due to modification of the same toolkit. This results in loss of Ca2+ homeostasis that can either cause or amplify the disease process.

  60. Neuroscience - development/plasticity/repair

    1. Cord blood mononuclear cells prevent neuronal apoptosis in response to perinatal asphyxia in the newborn lamb

      James D. S. Aridas, Courtney A. McDonald, Madison C. B. Paton, Tamara Yawno, Amy E. Sutherland, Ilias Nitsos, Yen Pham, Michael Ditchfield, Michael C. Fahey, Flora Wong, Atul Malhotra, Margie Castillo-Melendez, Kishore Bhakoo, Euan M. Wallace, Graham Jenkin and Suzanne L. Miller

      Article first published online: 14 DEC 2015 | DOI: 10.1113/JP271104

      Key points

      • Asphyxia at the time of birth is a significant cause of death or disability in newborns. There is very limited treatment available for these newborns.
      • Autologous umbilical cord blood (UBC) mononuclear cells reduce clinical markers of brain damage following perinatal asphyxia.
      • Autologous UBC mononuclear cells reduce neuroinflammation and neuronal apoptosis within the brain following perinatal asphyxia.
      • Autologous UBC mononuclear cells administered 12 h after perinatal asphyxia are neuroprotective, and a well-tolerated and feasible treatment for infants following hypoxic ischaemic encephalopathy.
  61. Molecular and cellular

    1. Mitochondria and carbon monoxide: cytoprotection and control of cell metabolism – a role for Ca2+?

      Sara R. Oliveira, Cláudia S. F. Queiroga and Helena L. A. Vieira

      Article first published online: 7 DEC 2015 | DOI: 10.1113/JP270955

      Thumbnail image of graphical abstract

      Carbon monoxide action on cellular targets: facts and hypotheses. CO inhibits Ca2+ channels located in the cytoplasmic membrane, promoting cytoprotection. At the mitochondrial level, CO has beneficial effects in a ROS-dependent manner: it decreases mitochondrial membrane permeabilization and consequently inhibits cell death, promotes mitochondrial metabolism and improves mitochondrial Ca2+ uptake ability. In the upper-right panel, it is hypothesized that CO is involved in Ca2+ balance between ER and mitochondria and that CO modulates mitochondrial metabolism via Ca2+ signalling.

    2. Proteolytic fragmentation of inositol 1,4,5-trisphosphate receptors: a novel mechanism regulating channel activity?

      Liwei Wang, Kamil J. Alzayady and David I. Yule

      Article first published online: 7 DEC 2015 | DOI: 10.1113/JP271140

      Thumbnail image of graphical abstract

      Conventional activation of IP3R results in intracellular Ca2+ signals with distinct features in terms of amplitude, frequency, initiation sites and duration of the signal as a consequence of regulation of channel activity by numerous cellular factors. In turn, these particular characteristics enable the activation of a specific subset of Ca2+ effector molecules and physiological outcomes (top panel). In this review we present evidence that proteolytic cleavage of IP3R by calpain and caspase does not necessary disable the channel, but consider that altered regulation of the cleaved channel may result in the generation of Ca2+ signals with distinct properties which encode specific cellular outcomes (bottom panel).

  62. Integrative

    1. Impact of extreme exercise at high altitude on oxidative stress in humans

      John Quindry, Charles Dumke, Dustin Slivka and Brent Ruby

      Article first published online: 7 DEC 2015 | DOI: 10.1113/JP270651

      Thumbnail image of graphical abstract

      Summary of oxidative stress responses to exercise and recovery at low and high altitudes Independent of altitude oxidative stress is induced by acute exercise in proportion to either exercise intensity or exercise duration. Redox balance, as indicated by depletion of endogenous antioxidants (AO) and production of reactive oxygen species (ROS), shifts toward oxidative stress during and following exercise at low and high altitudes (hiker symbol). Recent findings suggest that recovery (reclined stick figure) from high altitude exercise or ascension from low-to-high altitude is marked by an attenuated oxidative stress response as compared with recovery at lower elevations. Moreover, early findings indicate that redox-sensitive adaptations to exercise-induced oxidative stress may be negatively impacted by high altitude recovery. In contrast to exercise, healthy rested (inset) individuals at low altitude are often in redox balance and without oxidative stress.

  63. Neuroscience - behavioural/systems/cognitive

    1. You have free access to this content
      Use of a physiological profile to document motor impairment in ageing and in clinical groups

      S. R. Lord, K. Delbaere and S. C. Gandevia

      Article first published online: 7 DEC 2015 | DOI: 10.1113/JP271108

      Thumbnail image of graphical abstract

      Physiological profile for an individual older person showing performance scores expressed in z-score units in relation to the population aged 65 years and older. The profile indicates near average performances for proprioception, knee extension strength and reaction time and below average performances for visual contrast sensitivity and the standing and leaning balance tests. This information can be used to guide fall prevention strategies.

  64. Cardiovascular

    1. Retinal vascular imaging in early life: insights into processes and risk of cardiovascular disease

      Ling-Jun Li, Mohammad Kamran Ikram and Tien Yin Wong

      Article first published online: 23 NOV 2015 | DOI: 10.1113/JP270947

      Thumbnail image of graphical abstract

      The origins of CVD may be traced back to vascular and metabolic processes in early life. Retinal vascular imaging is a new technology that allows detailed non-invasive in vivo assessment and monitoring of the microcirculation. Our review supports the view that CVD risk factors are associated with structural and functional changes in the retinal microvasculature in early life. Thus, the microcirculation may be a site for pre-clinical processes underlying the development of CVD in adulthood.

  65. Muscle

    1. Beneficial effects of exercise on age-related mitochondrial dysfunction and oxidative stress in skeletal muscle

      Anna-Maria Joseph, Peter J. Adhihetty and Christiaan Leeuwenburgh

      Article first published online: 21 NOV 2015 | DOI: 10.1113/JP270659

      Thumbnail image of graphical abstract

      Mitochondria produce reactive oxygen species (ROS) during normal respiration, but when these free radicals accumulate, this leads to progressive damage to mitochondrial constituents including DNA, proteins and lipids. Mitochondrial DNA (mtDNA) mutations impair the synthesis of electron transport chain subunits and reduce oxidative phosphorylation. These changes cause mitochondrial dysfunction that affects a number of pathways vital for maintaining mitochondrial turnover and integrity such as biogenesis, dynamics (fusion and fission), autophagy–lysosomal degradation, and programmed cell death (apoptosis). Additionally, mitochondrial dysfunction through a vicious cycle causes further increases in ROS and oxidative damage, ultimately leading to a decline in muscle mass and strength, reduced physical function, and ageing.

  66. Integrative

    1. Ketamine suppresses hypoxia-induced inflammatory responses in the late-gestation ovine fetal kidney cortex

      Eileen I. Chang, Miguel A. Zárate, Maria B. Rabaglino, Elaine M. Richards, Maureen Keller-Wood and Charles E. Wood

      Article first published online: 15 NOV 2015 | DOI: 10.1113/JP271066

      Thumbnail image of graphical abstract
  67. Neuroscience - neurobiology of disease

    1. Kv3.3 potassium channels and spinocerebellar ataxia

      Yalan Zhang and Leonard K. Kaczmarek

      Article first published online: 15 NOV 2015 | DOI: 10.1113/JP271343

      Thumbnail image of graphical abstract

      Mutations in the Kv3.3 potassium channels produce spinocerebellar ataxia type 13, a disease that results in progressive degeneration of the cerebellum.

  68. Molecular and cellular

    1. TRPM2 protects against tissue damage following oxidative stress and ischaemia–reperfusion

      Barbara A. Miller and Joseph Y. Cheung

      Article first published online: 11 NOV 2015 | DOI: 10.1113/JP270934

      Thumbnail image of graphical abstract

      Although activation of the ion channel TRPM2 can induce cell death in some circumstances, TRPM2 can also preserve cell viability and protect against tissue damage following oxidative stress and ischaemia–reperfusion. TRPM2 dependent Ca2+ entry can modulate HIF-1/2α expression. One mechanism through which this may occur is through enhancement of calcineurin activity through TRPM2-dependent Ca2+ entry, which may increase HIF-1/2α stability. HIF-1/2α enhances expression of a number of target genes including those involved in energy metabolism, antioxidant expression and mitophagy. Ca2+ entry through TRPM2 may also directly influence mitochondrial Ca2+ uptake. Together, the impact on mitochondrial function results in reduced ROS production and reduced cell death. In contrast, in the TRPM2 KO, Ca2+ influx is reduced after oxidative stress and HIF-1/2α expression is decreased, as are proteins downstream of HIF-1/2α including BNIP3, SOD1/2, and NDUFA4L2. In addition, mitochondrial Ca2+ uptake is reduced, which may contribute to dysfunctional mitochondria along with decreased NDUFA4L2, and reduced mitochondrial bioenergetics. Decreased BNIP3, which results in reduced mitophagy, contributes to an accumulation of dysfunctional mitochondria and along with decreased SOD1/2 antioxidant activity, increased ROS. The cell has reduced tolerance to a further rise in ROS, for example following ischaemia or doxorubicin, leading to reduced cell survival and increased cell death in the absence of TRPM2.

  69. Cardiovascular

    1. Effect of resveratrol on metabolic and cardiovascular function in male and female adult offspring exposed to prenatal hypoxia and a high-fat diet

      Amin Shah, Laura M. Reyes, Jude S. Morton, David Fung, Jillian Schneider and Sandra T. Davidge

      Article first published online: 4 NOV 2015 | DOI: 10.1113/JP271133

      Thumbnail image of graphical abstract
  70. Integrative

    1. You have free access to this content
      The impact of age on cerebral perfusion, oxygenation and metabolism during exercise in humans

      Igor D. Braz and James P. Fisher

      Article first published online: 2 NOV 2015 | DOI: 10.1113/JP271081

      Thumbnail image of graphical abstract

      Putative mechanisms explaining the impact of age on the cerebral blood flow (CBF) responses to exercise. CO2, carbon dioxide; CMRO2, cerebral metabolic rate of oxygen; %VO2max, maximal oxygen consumption; NS, nervous system; EPR, exercise pressor reflex.

  71. Cardiovascular

    1. Diabetes and ageing-induced vascular inflammation

      Mariam El Assar, Javier Angulo and Leocadio Rodríguez-Mañas

      Article first published online: 2 NOV 2015 | DOI: 10.1113/JP270841

      Thumbnail image of graphical abstract

      Ageing and diabetes are two well-known cardiovascular risk factors that are associated with impaired vascular function, which in turn increases the risk of developing cardiovascular disease (CVD). Although many of the potential inflammatory mechanisms (circulating cytokines: tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6); enzymes: inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX); and the redox-sensitive pro-inflammatory nuclear factor κB (NF-κB)) implicated in vascular alteration associated with ageing overlap with those induced by diabetes, the co-existence of both entities results in greater inflammation and vascular dysfunction and therefore higher risk of CVD. From this fact arises the possibility of the existence of additional mechanisms of vascular damage that only manifest when diabetes and ageing co-exist, maybe related to a defective response through factors counteracting inflammation (nuclear related factor 2 (Nrf2) and sirtuins (SIRT)).

  72. Integrative

    1. Regulation of skeletal muscle blood flow during exercise in ageing humans

      Christopher M. Hearon Jr and Frank A. Dinenno

      Article first published online: 2 NOV 2015 | DOI: 10.1113/JP270593

      Thumbnail image of graphical abstract

      Simplified schematic diagram depicting the effects of impaired skeletal muscle vascular control with age in humans.

  73. Muscle

    1. Twenty-eight days of exposure to 3454 m increases mitochondrial volume density in human skeletal muscle

      Robert A. Jacobs, Anne-Kristine Meinild Lundby, Simone Fenk, Saskia Gehrig, Christoph Siebenmann, Daniela Flück, Niels Kirk, Matthias P. Hilty and Carsten Lundby

      Article first published online: 28 OCT 2015 | DOI: 10.1113/JP271118

      Thumbnail image of graphical abstract
  74. Integrative

    1. Gestational nanomaterial exposures: microvascular implications during pregnancy, fetal development and adulthood

      P. A. Stapleton

      Article first published online: 28 OCT 2015 | DOI: 10.1113/JP270581

      Thumbnail image of graphical abstract

      Maternal nanoparticle exposure may have consequences at anatomical sites throughout the fetomaternal system. Each compartment within the system (maternal, uterine, placental, umbilical and fetal) may be affected by nanoparticle translocation and deposition during gestation. These dysfunctions do not occur in a vacuum; they are not singular or mutually exclusive, but instead act uniquely within each exposure and pregnancy culminating in a hostile gestational environment which has been shown to affect fetal growth and development. These outcomes, which may continue into adulthood, increase cardiovascular disease susceptibility, thereby shortening the lifespan or accelerate aging of future generations.

  75. Research Paper

    1. You have full text access to this OnlineOpen article
      Placental phenotype and resource allocation to fetal growth are modified by the timing and degree of hypoxia during mouse pregnancy

      J. S. Higgins, O. R. Vaughan, E. Fernandez de Liger, A. L. Fowden and A. N. Sferruzzi-Perri

      Article first published online: 26 OCT 2015 | DOI: 10.1113/JP271057

      Thumbnail image of graphical abstract
  76. Cardiovascular

    1. Ageing, metabolism and cardiovascular disease

      Sarah Costantino, Francesco Paneni and Francesco Cosentino

      Article first published online: 22 OCT 2015 | DOI: 10.1113/JP270538

      Thumbnail image of graphical abstract

      Diagram showing the interconnection between ageing, metabolic impairment and cardiovascular disease. An array of molecular events affects cellular homeostasis during the life course, thus fostering accumulation free radicals, mitochondrial damage as well as maladaptive insulin signalling. These processes, in turn, favour the development of cardiometabolic states such as obesity, type 2 diabetes and adverse cardiovascular phenotypes.

  77. Neuroscience – development/plasticity/repair

    1. Membrane lipid rafts and neurobiology: age-related changes in membrane lipids and loss of neuronal function

      Junji Egawa, Matthew L. Pearn, Brian P. Lemkuil, Piyush M. Patel and Brian P. Head

      Article first published online: 14 OCT 2015 | DOI: 10.1113/JP270590

      Thumbnail image of graphical abstract

      Summary illustrating how age-related changes in the biochemistry and biophysical properties of the neuronal plasma membrane decrease MLRs, Cav-1 expression, and MLR-localized expression of neuronal receptors necessary for plasticity. A, normal adult neuronal plasma membranes (PMs) have an asymmetric cholesterol distribution (∼85% in the cytofacial and ∼15% in the exofacial leaflet), GM1 gangliosides in the exofacial leaflet, functional MLR microdomains, normal expression of Cav-1 and MLR-localized functional receptors necessary for growth and plasticity. B, during the ageing process, neuronal PMs exhibit a redistribution of cholesterol from the cytofacial to the exofacial leaflet, decreased GM1 gangliosides in the exofacial leaflet, loss of MLRs, decreased Cav-1 protein expression, and decreased receptor localization to MLRs, thus reducing the ability to evoke plasticity to an ever changing environment.

  78. SYMPOSIUM REVIEW

    1. Non-canonical roles for caveolin in regulation of membrane repair and mitochondria: implications for stress adaptation with age

      Jan M. Schilling and Hemal H. Patel

      Article first published online: 14 OCT 2015 | DOI: 10.1113/JP270591

      Thumbnail image of graphical abstract

      Caveolae serve multiple roles in regulation of cell biology. In addition to the classic role in regulation of signalling molecules at the plasma membrane, we highlight two additional roles for caveolin in regulation of mitochondrial structure and function and membrane repair that may be critical to stress adaptation in ageing and disease.

  79. Integrative

    1. A 5′-upstream short open reading frame encoded peptide regulates angiotensin type 1a receptor production and signalling via the β-arrestin pathway

      Gina L.C. Yosten, Jun Liu, Hong Ji, Kathryn Sandberg, Robert Speth and Willis K. Samson

      Article first published online: 13 OCT 2015 | DOI: 10.1113/JP270567

      Thumbnail image of graphical abstract

      PEP7 interrupts angiotensin II-induced saline but water drinking: proposed mechanism of action. PEP7 interferes with the action of angiotensin II (Ang II) to stimulate sodium chloride drinking via an action on the non-G protein-coupled signal cascade leading to a reduction in peptide stimulated phosphorylation of extracellular regulated kinases 1/2 (Erk1/2). PEP7 does not interrupt the action of angiotensin II to stimulate water drinking, nor does it interfere with angiotensin II activation of Erk1/2 via the G protein-dependent pathway leading to activation of phospholipase C (PLC), protein kinase C (PKC), or the epidermal growth factor (EGF) receptor.

  80. Neuroscience - behavioural/systems/cognitive

    1. Physiological roles for the subfornical organ: a dynamic transcriptome shaped by autonomic state

      Charles Colin Thomas Hindmarch and Alastair V. Ferguson

      Article first published online: 13 OCT 2015 | DOI: 10.1113/JP270726

      Thumbnail image of graphical abstract

      This schematic diagram highlights the central role of the subfornical organ (SFO) as a CNS structure without the normal blood brain barrier which plays critical roles in sensing and integrating peripheral signals of body fluid and metabolic status which do not cross the normal blood brain barrier. It highlights the primary outputs of SFO neurons to other CNS autonomic control centres including the arcuate (ARC), paraventricular (PVN), supraoptic (SON), and median preoptic (MnPO) nuclei, as well as the organum vasculosum of the lamina terminalis (OVLT), through which these integrative SFO neurons influence autonomic outputs. This diagram also summarises data from transcriptomic analysis, highlighting the numbers of genes expressed in SFO, the numbers regulated by dehydration and food deprivation, as well as validated and yet to be validated targets.

  81. Integrative

    1. You have free access to this content
      Late gestational hypoxia and a postnatal high salt diet programs endothelial dysfunction and arterial stiffness in adult mouse offspring

      Sarah L. Walton, Reetu R. Singh, Tiffany Tan, Tamara M. Paravicini and Karen M. Moritz

      Article first published online: 12 OCT 2015 | DOI: 10.1113/JP271067

      Thumbnail image of graphical abstract
  82. Neuroscience: cellular/molecular

    1. Differential short-term regional effects of early high dose erythropoietin on white matter in preterm lambs after mechanical ventilation

      Samantha K. Barton, Annie R. A. McDougall, Jacqueline M. Melville, Timothy J. M. Moss, Valerie A. Zahra, Tammy Lim, Kelly J. Crossley, Graeme R. Polglase and Mary Tolcos

      Article first published online: 8 OCT 2015 | DOI: 10.1113/JP271376

      Thumbnail image of graphical abstract
  83. Integrative

    1. You have full text access to this OnlineOpen article
      Regulation of ventilatory sensitivity and carotid body proliferation in hypoxia by the PHD2/HIF-2 pathway

      Emma J. Hodson, Lynn G. Nicholls, Philip J. Turner, Ronan Llyr, James W. Fielding, Gillian Douglas, Indrika Ratnayaka, Peter A. Robbins, Christopher W. Pugh, Keith J. Buckler, Peter J. Ratcliffe and Tammie Bishop

      Article first published online: 6 OCT 2015 | DOI: 10.1113/JP271050

      Thumbnail image of graphical abstract

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