bluuebunny/crossref_metadata_2025 huggingface dataset:
An activated unfolded protein response promotes retinal degeneration and triggers an inflammatory response in the mouse retina
Authors: Rana T , Shinde V M , Starr C R , Kruglov A A , Boitet E R , Kotla P , Zolotukhin S , Gross A K , Gorbatyuk M S
Published: December 2014

Recent studies on the endoplasmic reticulum stress have shown that the unfolded protein response (UPR) is involved in the pathogenesis of inherited retinal degeneration caused by mutant rhodopsin. However, the main question of whether UPR activation actually triggers retinal degeneration remains to be addressed. Thus, in this study, we created a mouse model for retinal degeneration caused by a persistently activated UPR to assess the physiological and morphological parameters associated with this disease state and to highlight a potential mechanism by which the UPR can promote retinal degeneration. We performed an intraocular injection in C57BL6 mice with a known unfolded protein response (UPR) inducer, tunicamycin (Tn) and examined animals by electroretinography (ERG), spectral domain optical coherence tomography (SD-OCT) and histological analyses. We detected a significant loss of photoreceptor function (over 60%) and retinal structure (35%) 30 days post treatment. Analysis of retinal protein extracts demonstrated a significant upregulation of inflammatory markers including interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and IBA1. Similarly, we detected a strong inflammatory response in mice expressing either Ter349Glu or T17M rhodopsin (RHO). These mutant rhodopsin species induce severe retinal degeneration and T17M rhodopsin elicits UPR activation when expressed in mice. RNA and protein analysis revealed a significant upregulation of pro- and anti-inflammatory markers such as IL-1β, IL-6, p65 nuclear factor kappa B (NF-kB) and MCP-1, as well as activation of F4/80 and IBA1 microglial markers in both the retinas expressing mutant rhodopsins. We then assessed if the Tn-induced inflammatory marker IL-1β was capable of inducing retinal degeneration by injecting C57BL6 mice with a recombinant IL-1β. We observed ~19% reduction in ERG a-wave amplitudes and a 29% loss of photoreceptor cells compared with control retinas, suggesting a potential link between pro-inflammatory cytokines and retinal pathophysiological effects. Our work demonstrates that in the context of an established animal model for ocular disease, the persistent activation of the UPR could be responsible for promoting retinal degeneration via the UPR-induced pro-inflammatory cytokine IL-1β.
Distinct aspects of frontal lobe structure mediate age-related differences in fluid intelligence and multitasking
Authors: Kievit Rogier A. , Davis Simon W. , Mitchell Daniel J. , Taylor Jason R. , Duncan John ,   Cam-CAN Research team, Tyler Lorraine K. , Brayne Carol , Bullmore Ed , Calder Andrew , Cusack Rhodri , Dalgleish Tim , Matthews Fiona , Marslen-Wilson William , Rowe James , Shafto Meredith , Campbell Karen , Cheung Teresa , Geerligs Linda , McCarrey Anna , Tsvetanov Kamen , Williams Nitin , Bates Lauren , Emery Tina , Erzinçlioglu Sharon , Gadie Andrew , Gerbase Sofia , Georgieva Stanimira , Hanley Claire , Parkin Beth , Troy David , Allen Jodie , Amery Gillian , Amunts Liana , Barcroft Anne , Castle Amanda , Dias Cheryl , Dowrick Jonathan , Fair Melissa , Fisher Hayley , Goulding Anna , Grewal Adarsh , Hale Geoff , Hilton Andrew , Johnson Frances , Johnston Patricia , Kavanagh-Williamson Thea , Kwasniewska Magdalena , McMinn Alison , Norman Kim , Penrose Jessica , Roby Fiona , Rowland Diane , Sargeant John , Squire Maggie , Stevens Beth , Stoddart Aldabra , Stone Cheryl , Thompson Tracy , Yazlik Ozlem , Barnes Dan , Dixon Marie , Hillman Jaya , Mitchell Joanne , Villis Laura , Henson Richard N.A.
Published: December 2014

Ageing is characterized by declines on a variety of cognitive measures. These declines are often attributed to a general, unitary underlying cause, such as a reduction in executive function owing to atrophy of the prefrontal cortex. However, age-related changes are likely multifactorial, and the relationship between neural changes and cognitive measures is not well-understood. Here we address this in a large (N=567), population-based sample drawn from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) data. We relate fluid intelligence and multitasking to multiple brain measures, including grey matter in various prefrontal regions and white matter integrity connecting those regions. We show that multitasking and fluid intelligence are separable cognitive abilities, with differential sensitivities to age, which are mediated by distinct neural subsystems that show different prediction in older versus younger individuals. These results suggest that prefrontal ageing is a manifold process demanding multifaceted models of neurocognitive ageing.
Slow unloading leads to DNA-bound β2-sliding clamp accumulation in live Escherichia coli cells
Authors: Moolman M. Charl , Krishnan Sriram Tiruvadi , Kerssemakers Jacob W. J. , van den Berg Aafke , Tulinski Pawel , Depken Martin , Reyes-Lamothe Rodrigo , Sherratt David J. , Dekker Nynke H.
Published: December 2014

The ubiquitous sliding clamp facilitates processivity of the replicative polymerase and acts as a platform to recruit proteins involved in replication, recombination and repair. While the dynamics of the E. coli β2-sliding clamp have been characterized in vitro, its in vivo stoichiometry and dynamics remain unclear. To probe both β2-clamp dynamics and stoichiometry in live E. coli cells, we use custom-built microfluidics in combination with single-molecule fluorescence microscopy and photoactivated fluorescence microscopy. We quantify the recruitment, binding and turnover of β2-sliding clamps on DNA during replication. These quantitative in vivo results demonstrate that numerous β2-clamps in E. coli remain on the DNA behind the replication fork for a protracted period of time, allowing them to form a docking platform for other enzymes involved in DNA metabolism.
Functionally reciprocal mutations of the prolactin signalling pathway define hairy and slick cattle
Authors: Littlejohn Mathew D. , Henty Kristen M. , Tiplady Kathryn , Johnson Thomas , Harland Chad , Lopdell Thomas , Sherlock Richard G. , Li Wanbo , Lukefahr Steven D. , Shanks Bruce C. , Garrick Dorian J. , Snell Russell G. , Spelman Richard J. , Davis Stephen R.
Published: December 2014

Lactation, hair development and homeothermy are characteristic evolutionary features that define mammals from other vertebrate species. Here we describe the discovery of two autosomal dominant mutations with antagonistic, pleiotropic effects on all three of these biological processes, mediated through the prolactin signalling pathway. Most conspicuously, mutations in prolactin (PRL) and its receptor (PRLR) have an impact on thermoregulation and hair morphology phenotypes, giving prominence to this pathway outside of its classical roles in lactation.
Paternal heterochromatin formation in human embryos is H3K9/HP1 directed and primed by sperm-derived histone modifications
Authors: van de Werken Christine , van der Heijden Godfried W. , Eleveld Cindy , Teeuwssen Miriam , Albert Mareike , Baarends Willy M. , Laven Joop S. E. , Peters Antoine H. F. M. , Baart Esther B.
Published: December 2014

The different configurations of maternal and paternal chromatin, acquired during oogenesis and spermatogenesis, have to be rearranged after fertilization to form a functional embryonic genome. In the paternal genome, nucleosomal chromatin domains are re-established after the protamine-to-histone exchange. We investigated the formation of constitutive heterochromatin (cHC) in human preimplantation embryos. Our results show that histones carrying canonical cHC modifications are retained in cHC regions of sperm chromatin. These modified histones are transmitted to the oocyte and contribute to the formation of paternal embryonic cHC. Subsequently, the modifications are recognized by the H3K9/HP1 pathway maternal chromatin modifiers and propagated over the embryonic cleavage divisions. These results are in contrast to what has been described for mouse embryos, in which paternal cHC lacks canonical modifications and is initially established by Polycomb group proteins. Our results show intergenerational epigenetic inheritance of the cHC structure in human embryos.
Global solutions of certain plasma fluid models in three-dimension
Authors: Guo Yan , Ionescu Alexandru D. , Pausader Benoit
Published: December 2014

We consider several dispersive time-reversible plasma fluid models in 3 dimensions: the Euler-Poisson 2-fluid model, the relativistic Euler–Maxwell 1-fluid model, and the relativistic Euler–Maxwell 2-fluid model. In all of these models, we prove global stability of the constant background solutions, in the sense that small, smooth, and irrotational perturbations lead to smooth global solutions that decay as t → ∞.
From Toxic Wreck to Crunchy Chic: Environmental Gentrification through the Body
Authors: Kern Leslie
Published: December 2014

This paper takes up the challenge of extending and enhancing the literature on environmental gentrification by considering bodies and embodied practices as significant dimensions of this process. In considering the question of how a polluted past can be mobilized as an asset for neighbourhood rebranding and gentrification, this research suggests that the conflation of both pollution and ‘health’ with different kinds of urban bodies and practices is an important strategy for solidifying a clean and green neighbourhood future. I argue that some bodies are constituted as ‘dirty’ by the symbolic and substantive displacement of environmental pollution onto those bodies, in ways that allow the neighbourhood to redefine itself as clean (whether it is environmentally clean or not) once those bodies are displaced, contained, or made invisible. This perspective requires us to consider the radically coconstitutive character of representations and materiality, bodies and cities, nature and social relations. Based on a case study of Toronto's Junction neighbourhood, this paper maintains that bringing bodies to the foreground attends to the power of embodiment in producing and reproducing urban change and, critically, urban inequalities.
Reproductive seasonality in African ungulates in relation to rainfall
Authors: Ogutu Joseph O. , Piepho Hans-Peter , Dublin Holly T.
Published: December 2014

Context
Reproductive seasonality in ungulates has important fitness consequences but its relationship to resource seasonality is not yet fully understood, especially for ungulates inhabiting equatorial environments.

Aims
We test hypotheses concerning synchronisation of conception or parturition peaks among African ungulates with seasonal peaks in forage quality and quantity, indexed by rainfall.

Methods
We relate monthly apparent fecundity and juvenile recruitment rates to monthly rainfall for six ungulate species inhabiting the Masai Mara National Reserve (Mara) of Kenya, using cross-correlation analysis and distributed lag non-linear models. We compare the phenology and synchrony of breeding among the Mara ungulates with those for other parts of equatorial East Africa, with bimodal rainfall and less seasonal forage variation, and for subtropical southern Africa, with unimodal rainfall distribution and greater seasonal forage variation.

Key results
Births were more synchronised for topi, warthog and zebra than for hartebeest, impala and giraffe in the Mara, and for impala and hartebeest in southern than in eastern Africa. This pattern is likely to reflect regional differences in climate and plant phenology, hider–follower dichotomy and grazing versus browsing. All six species except the browsing giraffe apparently time the conception to occur in one wet season and births to occur just before the onset or during the next wet season, so as to maximise high-quality forage intake during conception and parturition. Fecundity and recruitment rates among the African ungulates peak at intermediate levels of rainfall and are reduced at low or excessive levels of rainfall. Fecundity rate is most strongly positively correlated with rainfall pre-conception, during conception and during early gestation, followed by rainfall at about the time of parturition for all the grazers. For giraffe, fecundity rate is most strongly correlated with rainfall during the gestation period.

Conclusions
Rainfall seasonality strongly influences reproductive seasonality and juvenile recruitment among African ungulates. The interaction of the rainfall influence with life-history traits and other factors leads to wide interspecific and regional variation.

Implications
Global climate change, especially widening annual rainfall variation expected to result from global warming, could reduce the predictability of the timing of peak forage availability and quality based on meteorological cues, the length of time with adequate nutrition or both, and hence reduce reproductive success among tropical ungulates.
Patterns of grassland productivity, composition and seed abundance, and the diet of the flock bronzewing pigeon Phaps histrionica at one site in northern Australia over a period of marked seasonal change
Authors: Dostine P. L. , Woinarski J. C. Z. , Mackey B. , Nix H.
Published: December 2014

Context
Multiple scales of research are needed to understand the ecology and conservation requirements of species whose ecology is characterised by marked spatial and temporal dynamism. The flock bronzewing pigeon may provide a model for the conservation management of species with similar dispersive ecologies.

Aims
This study aimed to document the species composition and its variability in seeds consumed by flock bronzewing pigeons across a period of contrasting seasonal conditions, and to relate this diet to variation in food resource availability.

Methods
The diet of the flock bronzewing pigeon was described by analysis of the crop contents of samples collected over the period from June 2006 to September 2007 at one pastoral property on the Barkly Tablelands, Northern Territory. Variation in food resource availability was assessed using data from remote sensing, grassland community structure, and direct measurement of soil seed density. Multivariate statistical methods were used to test variation in plant community structure between years and among land units; generalised linear modelling was used to examine inter-annual variation in the abundance of key food plant species and seasonal variation in seed abundance.

Key results
Across the period of this study, the diet of flock bronzewing pigeons on the Barkly Tableland was largely restricted to seeds of a small number of plant species within Mitchell grasslands. Dietary patterns varied between years; evidence from remote sensing, grassland community structure, and seed density was consistent with these dietary patterns.

Conclusions
Flock bronzewing pigeons appear to be adapted to exploiting rare, episodic events, leading to high seed production by the ephemeral or annual component of perennial tussock grasslands. Key food plant species include the forbs Wedelia asperrima, Trichodesma zeylanicum and Phyllanthus lacerosus and the large-seeded annual grass Chionachne hubbardiana. These species may not be those that provide critical resources during unfavourable periods.

Implications
Conservation management of flock bronzewing pigeons will entail strategies to maintain key food species in grazed landscapes, and to ensure replenishment of seed reserves of annual and ephemeral plant species. Management practices to achieve these goals may include rotational wet season spelling of paddocks. More information is required on the focal areas for persistence within these black-soil grassland landscapes.
A small-molecule mimic of a peptide docking motif inhibits the protein kinase PDK1
Authors: Rettenmaier T. Justin , Sadowsky Jack D. , Thomsen Nathan D. , Chen Steven C. , Doak Allison K. , Arkin Michelle R. , Wells James A.
Published: December 2014

Significance

Allosteric sites in protein kinases offer opportunities for developing more selective inhibitors, but these sites are challenging to target because they involve protein–protein interfaces. We designed a site-directed approach to screen for molecules that bind to an allosteric peptide docking site on the protein kinase PDK1. We discovered molecules that structurally mimic the natural peptide ligand and inhibit PDK1 in cells. We also found that combining allosteric and ATP-competitive inhibitors completely blocked the activation of oncogenic kinases downstream of PDK1. This approach could be adapted to target an analogous allosteric site found on many other kinases.
Structural basis of HIV-1 capsid recognition by PF74 and CPSF6
Authors: Bhattacharya Akash , Alam Steven L. , Fricke Thomas , Zadrozny Kaneil , Sedzicki Jaroslaw , Taylor Alexander B. , Demeler Borries , Pornillos Owen , Ganser-Pornillos Barbie K. , Diaz-Griffero Felipe , Ivanov Dmitri N. , Yeager Mark
Published: December 2014

Significance

Events that occur between entry of the HIV-1 capsid into the cytoplasm of the target cell and the delivery of the viral genetic material into the nucleus constitute some of the less well understood processes in the viral life cycle. We demonstrated that PF74, a small-molecule inhibitor of HIV-1, and the host proteins CPSF6 and NUP153 bind to a preformed pocket within the CA protein hexamers that exist within the assembled capsid. Our results suggest that key features of the CA hexameric lattice remain intact upon docking at the nuclear pore. In addition, low molecular weight ligands that better mimic virus–host, protein–protein interactions at the intersubunit interfaces within the assembled viral capsid may offer novel avenues for therapeutic intervention.
Who are the independent editors, how did they reach their role and what are their associated job satisfactions?
Authors: BAVERSTOCK Alison , BLACKBURN Robert , ISKANDAROVA Marfuga
Published: December 2014

This paper presents new evidence on the world of the independent editor in the publishing industry, analysing their demographic background, education and training, working practices, links with professional organizations, motivations for ‘going it alone‘, and job satisfaction. The results help contribute to the understanding of this important and growing segment of the publishing industry, challenge some of the commonly held beliefs about their role in the industry and set these within the broader context of changes in work organization in publishing. Contrary to the assumption that self‐publishing largely takes place without the involvement of an editor, research into the processes of self‐publishing (previously published in this journal) found that editors (and other providers of publishing services) were in fact often involved. The results are significant for the traditional publishing industry, the users of independent editorial services, and the editors themselves.
Identifying legitimate open access journals: some suggestions from a publisher
Authors: HILL Tom
Published: December 2014

Key points

New publishing models lead to new players – not all of them good.

No commonly accepted criteria aid scholars to select ‘good’ journals.

Journals (and publishers) need to assert their good practice.

How do publishers serve their different customers – readers, authors, reviewers, and the public?
Evolution of the Transfer Code of Practice
Authors: PHILLPOTTS James , DEVENPORT Tim , MITCHELL Alison
Published: December 2014

The Transfer Code of Practice was launched in 2008 as a set of best‐practice guidelines to be followed when a journal changes publisher, with the aim of ensuring uninterrupted access to content for subscribers. The Code has now been updated to reflect the continued evolution of the academic publishing process driven by new technologies, policies, and publishing practices.
PAR3 and aPKC regulate Golgi organization through CLASP2 phosphorylation to generate cell polarity
Authors: Matsui Toshinori , Watanabe Takashi , Matsuzawa Kenji , Kakeno Mai , Okumura Nobumasa , Sugiyama Ikuko , Itoh Norimichi , Kaibuchi Kozo
Published: December 2014

The organization of the Golgi apparatus is essential for cell polarization and its maintenance. The polarity regulator PAR complex (PAR3, PAR6, and aPKC) plays critical roles in several processes of cell polarization. However, how the PAR complex participates in regulating the organization of the Golgi remains largely unknown. Here we demonstrate the functional cross-talk of the PAR complex with CLASP2, which is a microtubule plus-end–tracking protein and is involved in organizing the Golgi ribbon. CLASP2 directly interacted with PAR3 and was phosphorylated by aPKC. In epithelial cells, knockdown of either PAR3 or aPKC induced the aberrant accumulation of CLASP2 at the trans-Golgi network (TGN) concomitantly with disruption of the Golgi ribbon organization. The expression of a CLASP2 mutant that inhibited the PAR3-CLASP2 interaction disrupted the organization of the Golgi ribbon. CLASP2 is known to localize to the TGN through its interaction with the TGN protein GCC185. This interaction was inhibited by the aPKC-mediated phosphorylation of CLASP2. Furthermore, the nonphosphorylatable mutant enhanced the colocalization of CLASP2 with GCC185, thereby perturbing the Golgi organization. On the basis of these observations, we propose that PAR3 and aPKC control the organization of the Golgi through CLASP2 phosphorylation.
Modelling fishers' response to discard prevention strategies: the case of the North Sea saithe fishery
Authors: Simons Sarah Laura , Döring Ralf , Temming Axel
Published: December 2014

Designing effective management plans requires understanding fishers' behaviour under that plan, because fishers change their behaviour in response to economic and management incentives, which in turn will lead to different fishery outcomes. This study presents a modelling framework for management strategy evaluations which takes into account the response of fishers to management schemes. Based on the upcoming discard ban, two discard prevention strategies were tested for the North Sea saithe fishery, where fleet segments have either no or a generally low quota for cod. Costs and benefits were assessed under the current management, a non-flexible system, where fleet segments had to stop fishing once the cod quota was reached and a flexible system where quota of saithe could be used to cover over-quota catch of cod at a ratio 1:5. The flexible scenario was beneficial both in protecting the North Sea saithe and cod stock and in increasing net profits of fleet segments in the long term. The avoidance behaviour of fleet segments to over-quota catch led to a high SSB level of saithe and cod in the long term, ensuring high long-term catches and profits. A non-flexible scenario had a negative impact on the saithe stock, because mainly juvenile saithe before spawning were caught reducing the spawning-stock biomass in the longer term. A non-flexible scenario was costly in terms of up to 29% lower net profits for individual fleet segments generating little economic incentive to be compliant.
Galactic hail: the origin of the high-velocity cloud complex C
Authors: Fraternali F. , Marasco A. , Armillotta L. , Marinacci F.
Published: December 2014

High-velocity clouds consist of cold gas that appears to be raining down from the halo to the disc of the Milky Way. Over the past 50 years, two competing scenarios have attributed their origin either to gas accretion from outside the Galaxy or to circulation of gas from the Galactic disc powered by supernova feedback (galactic fountain). Here, we show that both mechanisms are simultaneously at work. We use a new galactic fountain model combined with high-resolution hydrodynamical simulations. We focus on the prototypical cloud complex C and show that it was produced by an explosion that occurred in the Cygnus-Outer spiral arm about 150 Myr ago. The ejected material has triggered the condensation of a large portion of the circumgalactic medium and caused its subsequent accretion on to the disc. This fountain-driven cooling of the lower Galactic corona provides the low-metallicity gas required by chemical evolution models of the Milky Way's disc.
The deep sea is a major sink for microplastic debris
Authors: Woodall Lucy C. , Sanchez-Vidal Anna , Canals Miquel , Paterson Gordon L.J. , Coppock Rachel , Sleight Victoria , Calafat Antonio , Rogers Alex D. , Narayanaswamy Bhavani E. , Thompson Richard C.
Published: December 2014

Marine debris, mostly consisting of plastic, is a global problem, negatively impacting wildlife, tourism and shipping. However, despite the durability of plastic, and the exponential increase in its production, monitoring data show limited evidence of concomitant increasing concentrations in marine habitats. There appears to be a considerable proportion of the manufactured plastic that is unaccounted for in surveys tracking the fate of environmental plastics. Even the discovery of widespread accumulation of microscopic fragments (microplastics) in oceanic gyres and shallow water sediments is unable to explain the missing fraction. Here, we show that deep-sea sediments are a likely sink for microplastics. Microplastic, in the form of fibres, was up to four orders of magnitude more abundant (per unit volume) in deep-sea sediments from the Atlantic Ocean, Mediterranean Sea and Indian Ocean than in contaminated sea-surface waters. Our results show evidence for a large and hitherto unknown repository of microplastics. The dominance of microfibres points to a previously underreported and unsampled plastic fraction. Given the vastness of the deep sea and the prevalence of microplastics at all sites we investigated, the deep-sea floor appears to provide an answer to the question—
where is all the plastic?
Organization of electrical activity in the canine pyloric canal.
Authors: Sanders K M , Vogalis F
Published: December 2014

1. The electrical activity of the canine gastroduodenal junction was investigated using cross‐sectional muscle preparations and intracellular recording techniques. 2. Spontaneous electrical slow waves were recorded from antral and pyloric cells but not from duodenal cells adjacent to the pyloric region. Slow waves were generated in the antrum and propagated to the pyloric region via the circular layer. Pyloric slow waves consisted of an upstroke phase, a plateau phase and oscillations superimposed upon the plateau, whereas antral slow waves had smooth plateau potentials. 3. Within the pylorus slow waves decayed in amplitude with distance from the myenteric border of the circular muscle; the majority of pyloric circular cells were normally electrically quiescent. 4. The longitudinal muscle in the pylorus was electrically coupled and paced by the circular muscle. In longitudinal cells slow waves were usually of long duration with multiple spikes superimposed upon the plateau phase. 5. Nifedipine (10(‐8) to 10(‐5) M) decreased slow waves amplitude and duration. Tetraethylammonium ions (TEA; 10 mM) increased the duration of slow waves, caused spiking activity during the plateau phase and also elicited spiking in the quiescent regions. 6. The results suggest that gastric slow waves pace the myenteric portion of the circular muscle layer and the longitudinal layer of the pylorus, but do not traverse the gastroduodenal junction, nor pace the majority of cells within the circular muscle of the pylorus. Other excitatory mechanisms are necessary to activate these regions and to co‐ordinate their motility with gastric motility.
Plasmapheresis affects responses of slowly and rapidly adapting airway receptors to pulmonary venous congestion in dogs.
Authors: Kappagoda C T , Ravi K
Published: December 2014

1. The effects of plasmapheresis on the responses of rapidly adapting receptors (RARs) and slowly adapting receptors (SARs) of the airways to pulmonary venous congestion were examined in dogs anaesthetized with alpha‐chloralose. Pulmonary venous congestion was produced in a graded manner by partial obstruction of the mitral valve sufficient to raise the mean left atrial pressure by 5, 10 and 15 mmHg. Plasmapheresis was performed by withdrawing 10% of blood volume twice. 2. Both RARs (n = 11) and SARs (n = 5) responded to pulmonary venous congestion by increasing their activities. The responses of the former were proportionately greater. 3. After plasmapheresis which reduced the concentration of plasma proteins by 12.3 +/‐ 1.0%, the responses of the RARs to pulmonary venous congestion were enhanced significantly. There was no significant change in the responses of SARs. 4. In another set of six RARs, the effects of graded pulmonary venous congestion were investigated twice with an interval of 45 min between the two observations. No significant differences were noted between the two responses. 5. Collection of lymph from the tracheobronchial lymph duct (n = 6) showed that after plasmapheresis, there was an increase in the control lymph flow. In addition, the lymph flow was enhanced during pulmonary venous congestion (mean left atrial pressure increased by 10 mmHg). 6. It is suggested that a natural stimulus for the excitation of the RAR is a function of the fluid fluxes in the pulmonary extravascular space.
Effect of sympathetic nerves on composition and distensibility of cerebral arterioles in rats.
Authors: Baumbach G L , Heistad D D , Siems J E
Published: December 2014

1. The goals of this study were to examine the effects of chronic sympathetic denervation on the mechanics and composition of cerebral arterioles in normotensive Wistar Kyoto rats (WKY) and stroke‐prone spontaneously hypertensive rats (SHRSP). 2. We used an in vivo method to examine the mechanics of pial arterioles in 10‐ to 12‐month‐old, anaesthetized WKY and SHRSP that had undergone unilateral removal of the superior cervical ganglion at 1 month of age. Bilateral craniotomies were performed in each rat to expose pial arterioles in the innervated and denervated cerebral hemispheres. Arterioles were deactivated with EDTA. Incremental distensibility and stress‐strain relationships were calculated from measurements of pial arteriolar pressure (servo null), diameter and cross‐sectional area of the arteriolar wall. Point counting stereology was used to quantify volume density and cross‐sectional area of individual components in the arteriolar wall. 3. Chronic sympathetic denervation reduced cross‐sectional area of the arteriolar wall by 16 +/‐ 2% (mean +/‐ S.E. of mean; P less than 0.05) in WKY and 44 +/‐ 3% in SHRSP. During maximal dilatation with EDTA, incremental distensibility was reduced and the stress‐strain curve was shifted to the left in denervated arterioles of SHRSP, but not WKY. These findings indicate that sympathetic denervation in SHRSP attenuates the development of hypertrophy in pial arterioles and reduces arteriolar distensibility. The ratio of non‐distensible (collagen and basement membrane) to distensible (smooth muscle, elastin and endothelium) components was reduced in denervated arterioles in SHRSP, but not WKY. 4. Thus, sympathetic nerves have trophic effects on cerebral arterioles in WKY and, to a greater degree, in SHRSP. Sympathetic nerves also contribute to increases in distensibility of cerebral arterioles in SHRSP, but not WKY. The increase in arteriolar distensibility is accompanied by a disproportionate increase in the more compliant elements of cerebral arterioles.
Low‐voltage‐activated calcium current in rat aorta smooth muscle cells in primary culture.
Authors: Akaike N , Kanaide H , Kuga T , Nakamura M , Sadoshima J , Tomoike H
Published: December 2014

1. Electrical and pharmacological properties of the low‐voltage‐activated Ca2+ current (ICa, LVA) in rat aorta smooth muscle cells (SMC) in primary culture were examined, particularly in comparison with the high‐voltage‐activated Ca2+ current (ICa, HVA). Both types of Ca2+ currents were recorded in external solution containing 20 mM‐Ca2+, using the whole‐cell voltage‐clamp technique. 2. ICa, LVA was evoked by step depolarizations to potentials more positive than ‐60 mV from a holding potential of ‐100 mV, and reached a peak in the current‐voltage (I‐V) relationship around ‐30 mV. ICa, HVA was activated at ‐20 mV, and reached a peak at +20 mV. 3. The intracellular dialysis of 5 mM‐F‐ irreversibly suppressed ICa, HVA, with time, while it has little effect on the ICa, LVA. The ICa, LVA could be separated from the ICa, HVA by either selecting the holding and test potential levels or by perfusing intracellularly with F‐. 4. The ratio of peak amplitude of Ba2+, Sr2+ and Ca2+ currents in the respective I‐V relationship was 1.6:1.2:1.0 for high‐voltage‐activated Ca2+ channels and was 1.0:1.4:1.0 for low‐voltage‐activated ones. 5. The inactivation phase of ICa, HVA was fitted by a sum of double‐exponential functions, the time constants of which were larger when the current was carried by Ba2+ than by Ca2+. The inactivation time course of ICa, LVA was fitted by a single‐exponential function, and the time constant was practically the same when the current was carried by Ba2+ or by Ca2+. Activation and inactivation processes of ICa, LVA were potential‐dependent. 6. The steady‐state inactivation curve of ICa, LVA was fitted by the Boltzmann equation, having a mid‐potential of ‐80 mV and a slope factor of 5.0. The recovery time course from steady‐state inactivation was fitted by a sum of two exponential functions. The time constants of the faster phase were 230 and 380 ms, and those of slower phase were 2.8 and 1.8 s at the repolarization potentials of ‐120 and ‐100 mV, respectively. 7. The amplitude of ICa, LVA depended on the external Ca2+ concentration ([Ca2+]o), approaching saturation at 95 mM [Ca2+]o. 8. Various polyvalent cations blocked both types of Ca2+ current reversibly in the order (IC50 in M): La3+ (8 x 10(‐8)) greater than Cd2+ (6 x 10(‐6)) greater than Ni2+ (1 x 10(‐5)) greater than Zn2+ (2 x 10(‐5)) for ICa, HVA, and La3+ (6 x 10(‐7)) greater than Zn2+ (3 x 10(‐5)) greater than Cd2+ (4 x 10(‐4)) greater than Ni2+ (6 x 10(‐4)) for ICa, LVA.(ABSTRACT TRUNCATED AT 400 WORDS)
Cytoplasmic calcium as the messenger for light adaptation in salamander rods.
Authors: Fain G L , Lamb T D , Matthews H R , Murphy R L
Published: December 2014

1. In order to study the role of cytoplasmic calcium concentration (Ca2+i) in rod photoreceptor light adaptation, we have attempted to prevent light‐induced changes in Ca2+i by minimizing calcium fluxes across the outer segment plasma membrane. This was achieved by exposing the outer segment to a low‐Ca2+, 0‐Na+ solution, in which sodium was replaced with either guanidinium or lithium and the external calcium concentration (Ca2+o) was reduced to micromolar levels. 2. With guanidinium and 1‐3 microM‐Ca2+o, the circulating current in darkness was maintained for a period of at least 15 s, consistent with approximate stability of Ca2+i. With Li+ rather than guanidinium most of the initial current was suppressed, but the residual current was again relatively stable. 3. During prolonged exposures (greater than 30 s) to low‐Ca2+, 0‐Na+ solution followed by dim illumination, the circulating current did not remain constant but slowly increased. Incorporation of calcium buffer into the cytoplasm greatly reduced the rate of change of current, consistent with the idea that the increase arose from a gradual decrease in Ca2+i. 4. Light responses of rods exposed to low‐Ca2+, 0‐Na+ solution in darkness were altered in a characteristic manner. Although the initial rising phase of the light response was little changed, the peak amplitude of the response was larger and occurred later, and the response decayed more slowly than in control. The response‐intensity relation was steepened and was shifted towards lower intensities both for flashes and for steps of light. The normal sag in the response to steps disappeared, and the waveform of the step response could be predicted to a close approximation from the integral of the dim flash response. 5. Presentation of background illumination in Ringer solution produced a marked acceleration of the response to a subsequent bright flash. No such acceleration was observed if the background was given in low‐Ca2+, 0‐Na+ solution. 6. The results described in paragraphs 4 and 5 indicate that, under conditions expected to minimize changes in Ca2+i, all manifestations of light adaptation disappear, and the rod simply sums the effects of incident photons with an invariant integration time. 7. Exposure of a light‐adapted rod to low‐Ca2+, 0‐Na+ solution altered the responses to superimposed test flashes in much the same way as for rods in darkness. The initial rising phases in low‐Ca2+, 0‐Na+ solution were unchanged, but the responses were larger, reached peak later and decayed more slowly.(ABSTRACT TRUNCATED AT 400 WORDS)
Maximal shortening velocities, isomyosins and fibre types in soleus muscle of mice, rats and guinea‐pigs.
Authors: Asmussen G , Maréchal G
Published: December 2014

1. Guinea‐pig soleus contains only type I fibres and slow isomyosin, SM2. Rat and mouse soleus contain about 70% of type I fibres and a mixture of isomyosins: slow, SM2 and intermediate, IM. Many rat soleus muscles contain a third isomyosin of a slow type, SM1. 2. The maximal velocity of unloaded shortening, V0, is largest in mouse soleus (6.11 Lf s‐1), slowest in guinea‐pig soleus (1.67 Lf s‐1) and intermediate in rat soleus (4.16 Lf s‐1) (Lf = fibre length). 3. In guinea‐pig soleus, V0 is equal to the maximal velocity (Vmax) computed using the Hill force‐velocity relationship; V0 is approximately twice as large as Vmax in mouse and rat soleus. 4. V0 measures the unloaded shortening velocity of the fastest fibres whereas Vmax is a function of the force‐velocity characteristics of all the fibres contained in the muscle. 5. V0 increases according to the isomyosin composition of the fibres in the sequence SM2 less than SM1 + IM less than IM.
Spinal mechanisms in man contributing to reciprocal inhibition during voluntary dorsiflexion of the foot.
Authors: Crone C , Nielsen J
Published: December 2014

1. The inhibition of the soleus Hoffmann reflex (H reflex) during voluntary dorsiflexion of the foot‐‐henceforth referred to as ‘natural’ reciprocal inhibition‐‐was found to be initiated 50 ms before the onset of the EMG activity in the tibialis anterior muscle and to increase gradually during a ramp‐and‐hold dorsiflexion. There was a positive correlation between strength of tonic dorsiflexion and amount of ‘natural’ reciprocal inhibition. 2. The change of activity in the disynaptic and a long‐latency group Ia inhibitory pathway and the change in presynaptic inhibition of the Ia fibres mediating the soleus H reflex were tested separately during ramp‐and‐hold dorsiflexion as well as during tonic dorsiflexion of the foot, and the results were compared with the development of the ‘natural’ reciprocal inhibition of the unconditioned soleus H reflex. 3. The disynaptic group I inhibition of soleus motoneurones was increased, as compared to rest, during the dynamic phase of a ramp‐and‐hold dorsiflexion movement, but the inhibition generally did not increase during tonic dorsiflexion of the foot. 4. The long‐latency group I inhibition was seen only during dorsiflexion of the foot. It appeared around 50 ms before tibial anterior EMG activity and there was a positive correlation between strength of tonic dorsiflexion and amount of this long‐latency inhibition. 5. Presynaptic inhibition of Ia afferents terminating on soleus motoneurones was estimated by an indirect method. The increase of presynaptic inhibition started soon after the onset of the ramp‐and‐hold dorsiflexion, and gradually became more pronounced during the ramp phase. The amount of presynaptic inhibition was positively correlated with strength of tonic dorsiflexion. 6. It is concluded that all investigated mechanisms may contribute to the ‘natural’ reciprocal inhibition and it seems that the different pathways are used differentially during different types of movement.
Giant synaptic potentials in immature rat CA3 hippocampal neurones.
Authors: Ben‐Ari Y , Cherubini E , Corradetti R , Gaiarsa J L
Published: December 2014

1. Intracellular recordings were made from rat CA3 hippocampal neurones in vitro during the first eighteen days of postnatal life. The cells had resting membrane potentials more negative than ‐51 mV, action potentials greater than 55 mV and membrane input resistances of 117 +/‐ 12 M omega. An unusual characteristic of these cells was the presence of spontaneous giant depolarizing potentials (GDPs) which were observed during the first eight postnatal (P) days in over 85% of neurones. They were less frequent between P9 and P12 (48%) and disappeared after P12. 2. The GDPs were synchronously generated by a population of neurones; they reversed polarity at ‐27 mV when recorded with KCl‐containing electrodes and at ‐51 mV with potassium acetate‐ or potassium methylsulphate‐filled electrodes. 3. The GDPs were blocked by bath application of bicuculline (10 microM) or picrotoxin (100‐200 microM). Exogenously applied gamma‐aminobutyric acid (GABA; 0.2‐1 mM) induced at resting membrane potential a bicuculline‐sensitive membrane depolarization which reversed polarity at ‐25 and ‐51 mV when recorded with KCl‐ or potassium methylsulphate‐filled electrodes respectively. 4. The GDPs were reduced in frequency or blocked by the N‐methyl‐D‐aspartate (NMDA) receptor antagonists DL‐2‐amino‐7‐phosphonoheptanoate (AP‐7; 50 microM), D(‐)2‐amino‐5‐phosphonovalerate (AP‐5, 10‐50 microM) and (+‐)3‐(2‐carboxypiperazin‐4‐yl)‐propyl‐1‐phosphonic acid (CPP, 10‐50 microM) or NMDA channel blockers phencyclidine (2 microM) and ketamine (20 microM). 5. Stimulation of the hilus during the first week of life evoked a GDP followed by a hyperpolarization. The GDPs were generated by a population of synchronized neurones and reversed polarity at ‐27 mV with KCl‐filled electrodes and at ‐52 mV with potassium acetate‐ or potassium methylsulphate‐containing electrodes. 6. Bath application of bicuculline (1‐10 microM) or picrotoxin (100‐200 microM) reversibly blocked the evoked GDPs in the majority of cells. The NMDA receptor antagonists AP‐5 (50 microM), AP‐7 (50 microM) and CPP (30 microM) usually reduced the amplitude and the duration of the evoked GDPs. In neurones in which evoked GDPs were blocked by bicuculline, a NMDA‐mediated component was revealed by increasing the strength or the frequency of stimulation. 7. During the second week of postnatal life, when spontaneous GDPs were extremely rare or absent, superfusion with bicuculline (10 microM) induced, as in adult slices, interictal discharges. These reversed polarity near 0 mV with KCl‐ or potassium acetate‐containing electrodes and were reduced in amplitude and duration by AP‐5 (50 microM).(ABSTRACT TRUNCATED AT 400 WORDS)
The coupled movements of sodium and chloride across the basolateral membrane of frog skin epithelium.
Authors: Fernandes P L , Ferreira H G , Ferreira K T
Published: December 2014

1. When frog skin epithelium was exposed to a chloride‐free solution bathing the basolateral side of the frog skin preparation the short‐circuit current fell and there was a simultaneous loss of chloride and water from its cells. This effect was partially blocked by furosemide when this drug was added to the basolateral bathing solution. 2. Under control conditions and when added to the solution bathing the basolateral side of the preparation furosemide had no effect on the ion and water contents of the frog skin epithelium. 3. Furosemide but not SITS (4‐acetamide‐4'‐isothiocyanate‐stilbene‐2,2'‐disulphonic acid) or amiloride blocked the recovery of short‐circuit current and the reuptake of chloride and water by preparations pre‐incubated with chloride‐free solution on the basolateral side. The recovery of the short‐circuit current was also blocked by the replacement of basolateral potassium by sodium. 4. The effect on the short‐circuit current of graded replacements by impermeant ions of sodium or chloride did not show saturation for concentrations of these ions up to their control values. 5. Replacement of basolateral potassium by sodium inhibited the short‐circuit current and the recovery observed when potassium was reintroduced in the basolateral bathing solution was blocked by furosemide. 6. The replacement of basolateral sodium or chloride by impermeant ions induced an immediate fall in the intracellular concentrations of both sodium and chloride suggesting that the transport system coupling the movements of the two ions across the basolateral membrane is operative under control conditions. 7. It is proposed that the coupled movements of sodium and chloride across the basolateral membrane of the frog skin epithelium are mediated by a sodium‐potassium‐2 chloride co‐transport system which under control conditions is very near equilibrium.
Effects of hypoxia and metabolic inhibition on the intracellular sodium activity of mammalian ventricular muscle.
Authors: MacLeod K T
Published: December 2014

1. Intracellular Na+ activity (aiNa) has been measured in Purkinje fibres from sheep heart and in ventricular muscle from rabbit heart during hypoxia and metabolic inhibition. The aiNa was measured using liquid sensor ion‐sensitive microelectrodes. 2. Hypoxia, produced by replacement of O2 with N2 in the superfusate, produced an increase in aiNa. This increase was larger if sucrose replaced glucose in the superfusing Tyrode solution. The increase in aiNa was accompanied by a small depolarization. Upon reoxygenation aiNa decreased and cells rapidly repolarized. 3. When oxidative phosphorylation was inhibited by application of 2 mM‐cyanide, aiNa increased. This increase was also accompanied by a small depolarization. Upon removal of cyanide, aiNa and membrane potential recovered to control levels. 4. After inhibiting glycolysis, by replacing glucose with 2‐deoxy‐D‐glucose, inhibition of oxidative phosphorylation (by addition of cyanide or exposure to hypoxia) produced a much more rapid increase in aiNa and a large contracture. The rise in aiNa and the occurrence of a contracture could not be inhibited by application of amiloride (1 mM) or tetrodotoxin (1 microgram ml‐1). Removal of cyanide or reoxygenation and replacement of glucose resulted in a rapid relaxation of the contracture and a slower decrease in aiNa. 5. The relative rates of increase in aiNa during metabolic inhibition were compared with the rate observed when Na+‐K+‐ATPase was inhibited by application of 10 mumols l‐1 of the cardio‐active steroid strophanthidin. The rate of increase of aiNa when both oxidative phosphorylation and glycolysis were inhibited was approximately twice that observed with only oxidative phosphorylation inhibited and approximately half that observed in the presence of 10 microM‐strophanthidin. 6. Cyanide, applied when aiNa had been elevated (i.e. during exposure to 10 microM‐strophanthidin to inhibit Na+‐K+‐ATPase), did not produce a contracture. The contracture observed in the presence of cyanide and 2‐deoxy‐D‐glucose still occurred when Ca2+ was removed from the superfusate.