bluuebunny/crossref_metadata_2025 huggingface dataset:
CD4 T Cell Depletion at the Cervix during HIV Infection Is Associated with Accumulation of Terminally Differentiated T Cells
Authors: Gumbi P. P. , Jaumdally S. Z. , Salkinder A. L. , Burgers W. A. , Mkhize N. N. , Hanekom W. , Coetzee D. , Williamson A. , Passmore J. S.
Published: October 2011

In blood, the accumulation of terminally differentiated (TD) T cells during HIV infection is associated with CD4 T cell loss and HIV disease progression. Here, we investigated the maintenance and functional characteristics of memory T cells at the cervix. We found that CD4 T cell depletion at the cervix mirrors CD4 depletion in blood. In all women, depletion of CD4 T cells at the cervix was associated with significant reductions in CD45RA
−
CCR7
+
(central memory [CM]) T cells and the accumulation of CD45RA
+
CCR7
−
(TD T cells). We determined whether inflammation in the genital tract was associated with the local differentiation of T cells at the cervix. In uninfected women, genital tract inflammation was associated with the accumulation of CD45RA
−
CCR7
+
CM CD4 T cells and reduced frequencies of CD45RA
+
CCR7
−
TD cells at the cervix. This finding may reflect the fact that, in the absence of HIV infection, TD T cells may be slowly lost in the presence of genital inflammation, while CD45RA
−
CCR7
+
CM T cells are recruited to replenish the diminishing CD4 T cell pool. Following global stimulation with phorbol myristate acetate (PMA)-ionomycin, we noted a significant interleukin 2 (IL-2) deficit in both cervical and blood CD4 T cells from HIV-infected women compared to uninfected women, while gamma interferon (IFN-γ) production was similar, irrespective of HIV status. Few HIV-infected women had detectable IFN-γ and IL-2 HIV-specific T cell responses at the cervix, and these responses were significantly lower in magnitude than the corresponding responses in blood. These data suggest that CD4 depletion was associated with the accumulation of terminally differentiated T cell phenotypes at the cervical mucosa defective in their ability to produce IL-2. CD4 depletion and compromised immunity at the cervix may be accompanied by progressive decline of central memory-like T cells and development of T cells toward terminally differentiated phenotypes.
Core Histones H2B and H4 Are Mobilized during Infection with Herpes Simplex Virus 1
Authors: Conn Kristen L. , Hendzel Michael J. , Schang Luis M.
Published: October 2011

The infecting genomes of herpes simplex virus 1 (HSV-1) are assembled into unstable nucleosomes soon after nuclear entry. The source of the histones that bind to these genomes has yet to be addressed. However, infection inhibits histone synthesis. The histones that bind to HSV-1 genomes are therefore most likely those previously bound in cellular chromatin. In order for preexisting cellular histones to associate with HSV-1 genomes, however, they must first disassociate from cellular chromatin. Consistently, we have shown that linker histones are mobilized during HSV-1 infection. Chromatinization of HSV-1 genomes would also require the association of core histones. We therefore evaluated the mobility of the core histones H2B and H4 as measures of the mobilization of H2A-H2B dimers and the more stable H3-H4 core tetramer. H2B and H4 were mobilized during infection. Their mobilization increased the levels of H2B and H4 in the free pools and decreased the rate of H2B fast chromatin exchange. The histones in the free pools would then be available to bind to HSV-1 genomes. The mobilization of H2B occurred independently from HSV-1 protein expression or DNA replication although expression of HSV-1 immediate-early (IE) or early (E) proteins enhanced it. The mobilization of core histones H2B and H4 supports a model in which the histones that associate with HSV-1 genomes are those that were previously bound in cellular chromatin. Moreover, this mobilization is consistent with the assembly of H2A-H2B and H3-H4 dimers into unstable nucleosomes with HSV-1 genomes.
Genome-Wide Association Study among Four Horse Breeds Identifies a Common Haplotype Associated with
In Vitro
CD3
+
T Cell Susceptibility/Resistance to Equine Arteritis Virus Infection
Authors: Go Yun Young , Bailey Ernest , Cook Deborah G. , Coleman Stephen J. , MacLeod James N. , Chen Kuey-Chu , Timoney Peter J. , Balasuriya Udeni B. R.
Published: October 2011

Previously, we have shown that horses could be divided into susceptible and resistant groups based on an
in vitro
assay using dual-color flow cytometric analysis of CD3
+
T cells infected with equine arteritis virus (EAV). Here, we demonstrate that the differences in
in vitro
susceptibility of equine CD3
+
T lymphocytes to EAV infection have a genetic basis. To investigate the possible hereditary basis for this trait, we conducted a genome-wide association study (GWAS) to compare susceptible and resistant phenotypes. Testing of 267 DNA samples from four horse breeds that had a susceptible or a resistant CD3
+
T lymphocyte phenotype using both Illumina Equine SNP50 BeadChip and Sequenom's MassARRAY system identified a common, genetically dominant haplotype associated with the susceptible phenotype in a region of equine chromosome 11 (ECA11), positions 49572804 to 49643932. The presence of a common haplotype indicates that the trait occurred in a common ancestor of all four breeds, suggesting that it may be segregated among other modern horse breeds. Biological pathway analysis revealed several cellular genes within this region of ECA11 encoding proteins associated with virus attachment and entry, cytoskeletal organization, and NF-κB pathways that may be associated with the trait responsible for the
in vitro
susceptibility/resistance of CD3
+
T lymphocytes to EAV infection. The data presented in this study demonstrated a strong association of genetic markers with the trait, representing
de facto
proof that the trait is under genetic control. To our knowledge, this is the first GWAS of an equine infectious disease and the first GWAS of equine viral arteritis.
Surrogate outcomes are associated with low methodological quality of studies of rheumatoid arthritis treated with antitumour necrosis factor agents: a systematic review
Authors: Nobre Moacyr Roberto Cuce , da Costa Frnanda Marques
Published: October 2011

Background

Surrogate endpoints may be used as substitutes for, but often do not predict clinically relevant events.

Objective

To assess the methodological quality of articles that present their conclusions based on clinically relevant or surrogate outcomes in a systematic review of randomised trials and cohort studies of patients with rheumatoid arthritis treated with antitumour necrosis factor (TNF) agents.

Methods

PubMed, Embase and Cochrane databases were searched. The Jadad score, the percentage of Consolidated Standards Of Reporting Trials (CONSORT) statement items adequately reported and levels-of-evidence (Center for Evidence-based Medicine, Oxford) were used in a descriptive synthesis.

Results

Among 88 articles appraised, 27 had surrogate endpoints, mainly radiographic, and 44 were duplicate publications; 74% of articles with surrogate and 39% of articles with clinical endpoints (p=0.006). Fewer articles with surrogate endpoints represented a high level of evidence (Level 1b, 33% vs 62%, p=0.037) and the mean percentage of CONSORT statement items met was also lower for articles with surrogate endpoints (62.5 vs 70.7, p=0.026). Although fewer articles with surrogate endpoints were randomised trials (63% vs 74%, p=0.307) and articles with surrogate endpoints had lower Jadad scores (3.0 vs 3.2, p=0.538), these differences were not statistically significant.

Conclusion

Studies of anti-TNF agents that report surrogate outcomes are of lesser methodological quality. As such, inclusion of such studies in evidence syntheses may bias results.
Palaeomagnetic and AMS study of the Tarfaya coastal basin, Morocco: an early Turonian palaeopole for the African plate
Authors: Ruiz-Martínez Vicente Carlos , Palencia-Ortas Alicia , Villalaín Juan José , McIntosh Gregg , Martín-Hernández Fátima
Published: October 2011

An early Turonian (
c.
93 Ma) anoxic, cyclic marine deposition is registered in the unfolded outcrops from the Tarfaya coastal basin, where very high sedimentation rates enable the investigation of past geomagnetic field record at high temporal resolution. One hundred and fourteen samples have been sampled along a 10.5 m vertical profile (
c.
200–500 ka) of orbital-scale forced sedimentation. Rock magnetic investigations reveal mineralogy principally controlled by diamagnetic and paramagnetic behaviour, along with very low concentrations of low-coercivity ferromagnetic material which is probably magnetite. A well-defined magnetic fabric can be seen with the minimum susceptibility axis perpendicular to the foliation plane, and magnetic lineation compatible with NW African palaeostress since sedimentation times and/or the palaeocurrent associated with upwelling system deposition. Magnetic signature has the potential for performing reliability checks of reversed tiny wiggles, which were found in four samples not considered for the tectonic analysis. Alternating field demagnetization shows a single, stable, low-coercivity directional component. The new palaeopole (
N
=88; PLat=64.3°, PLon=256.3°, A
95
=2.5°;
K
=38.7), obtained after moderate (
f
=0.8) inclination flattening correction, is the first early Turonian palaeopole for the NW African Craton. It can contribute to the 90 Ma-centred sliding window of the different proposed synthetic Apparent Polar Wander Paths.
The relations between felsic and mafic volcanic rocks in continental flood basalts of Ethiopia: implication for the thermal weakening of the crust
Authors: Ayalew Dereje
Published: October 2011

Sr and Nd isotopic compositions are presented for a Miocene bimodal basalt–rhyolite suite from north Shewa, central Ethiopian plateau. Whole-rock Rb–Sr isochron of the rhyolites yields an age of 20.7±2.4 Ma, marking the onset of volcanism in central Ethiopia
c.
20 Ma, 10 Ma after initial magmatism in the northern Ethiopian plateau. Initial
87
Sr/
86
Sr ratios slightly vary in the basalts as well as in the rhyolites, ranging from 0.70440 to 0.70641 and from 0.70563 to 0.70658, respectively. Initial
143
Nd/
144
Nd ratios show significant variations in the basalts (0.51248–0.51274), but remain nearly constant in the rhyolites (0.51273–0.51278). The Sr and Nd isotopic ratios of the basalts are interpreted to reflect their derivation from Afar plume contaminated by crustal materials (up to 15% contamination). The rhyolites evolved dominantly by fractional crystallization of mantle-derived basaltic magmas similar in composition to the exposed flood basalts.
Geochemistry of 24 Ma basalts from NE Egypt: source components and fractionation history
Authors: Endress Chira , Furman Tanya , El-Rus Mohamed Ali Abu , Hanan Barry B.
Published: October 2011

Subalkaline basalts from NE Egypt represent an episode of magmatism at
c
. 24 Ma, coincident with widespread eruptive activity in northern Africa. New geochemical data provide insight into the mineralogical and isotopic characteristics of the underlying mantle. The basalts show little geochemical variation, with incompatible trace element abundances similar to those of ocean island basalts. They display fairly smooth primitive mantle-normalized incompatible trace element patterns. Trace element abundances and Sr–Nd–Pb–Hf isotopic signatures are consistent with contributions from two distinct source regions, one similar to the Afar plume and the other located within the metasomatized spinel-facies subcontinental lithosphere. Mixing of melts from these two domains was followed by minor crustal contamination during prolonged ascent or emplacement. Integrating the geochemical data with available tomographic information allows us to develop a framework for understanding mid-Tertiary magmatic activity throughout northern Africa. A model for this widespread volcanism involves ascent of upwelling mantle derived from the margins of the South African Superplume rooted at the core–mantle boundary and/or through small-scale convection at the 660 km discontinuity. Ascent of magmas to the surface was facilitated by pre-existing structures within the lithosphere, including those associated with incipient rifting of the Red Sea.

Supplementary material:

Mineral chemistry data are available at
http://www.geolsoc.org.uk/SUP18483
.
The Mid-Miocene East African Plateau: a pre-rift topographic model inferred from the emplacement of the phonolitic Yatta lava flow, Kenya
Authors: Wichura Henry , Bousquet Romain , Oberhänsli Roland , Strecker Manfred R. , Trauth Martin H.
Published: October 2011

High topography in the realm of the rifted East African Plateau is commonly explained by two different mechanisms: (1) rift-flank uplift resulting from mechanical and/or isostatic relaxation and (2) lithospheric uplift due to the impingement of a mantle plume. High topography in East Africa has far-reaching effects on atmospheric circulation systems and the amount and distribution of rainfall in this region. While the climatic and palaeoenvironmental influences of high topography in East Africa are widely accepted, the timing, the magnitude and this spatiotemporal characteristic of changes in topography have remained unclear. This dilemma stems from the lack of datable, geomorphically meaningful reference horizons that could unambiguously record surface uplift. Here, we report on the formation of high topography in East Africa prior to Cenozoic rifting. We infer topographic uplift of the East African Plateau based on the emplacement characteristics of the
c.
300 km long and 13.5 Ma Yatta phonolitic lava flow along a former river valley that drained high topography, centred at the present-day rift. The lava flow followed an old riverbed that once routed runoff away from the eastern flank of the plateau. Using a compositional and temperature-dependent viscosity model with subsequent cooling and adjusting for the Yatta lava-flow dimensions and the covered palaeotopography (slope angle), we use the flow as a ‘palaeo-tiltmeter’. Based on these observations and our modelling results, we determine a palaeoslope of the Kenya dome of at least 0.2° prior to rifting and deduce a minimum plateau elevation of 1400 m. We propose that this high topography was caused by thermal expansion of the lithosphere interacting with a heat source generated by a mantle plume. Interestingly, the inferred Mid-Miocene uplift coincides with fundamental palaeoecological changes including the two-step expansion of grasslands in East Africa as well as important radiation and speciation events in tropical Africa.
Recent tectonics of Tripolitania, Libya: an intraplate record of Mediterranean subduction
Authors: Capitanio F. A. , Faccenna C. , Funiciello R. , Salvini F.
Published: October 2011

High-energy seismicity is historically recorded in Tripolitania, Libya suggesting that this area, far from Mediterranean convergent margin, is currently deforming. How this deformation relates to surrounding tectonics of the Africa-Europe convergence is still poorly known. Here, we use remote sensing image analysis and structural survey to show the recent deformation history that affected Tripolitania and reactivated the western bordering structures of Sirte Basin. This tectonic regime onset long after the Paleocene–Oligocene deformation correlated to the Hellenic subduction evolution (Libyan tectonics have been quiescent since then) and is compatible with age and trends of the Sicily Channel rift zone, a deformational belt that developed across the Maghrebian chain. We show that the continuity of this belt reaches farther than that previously acknowledged, as far as
c.
1400 km from the collisional front. We speculate on the causes of deformation in this remote area, suggesting that the extensional belt formed in response to the strong slab-pull gradients at the central Mediterranean subduction margin which followed the progressive closure of the oceanic basin.
The enigmatic Chad lineament revisited with global gravity and gravity-gradient fields
Authors: Braitenberg Carla , Mariani Patrizia , Ebbing Jörg , Sprlak Michal
Published: October 2011

The crustal structure of northern Africa is puzzling, large areas being of difficult access and concealed by the Sahara. The new global gravity models are of unprecedented precision and spatial resolution and offer a new possibility to reveal the structure of the lithosphere beneath the Sahara. The gravity gradients correlate better than gravity with geological features such as rifts, fold belts and magmatic deposits and intrusions. They are an ideal tool to follow geological units (e.g. basement units) below a stratigraphic layer of varying density (e.g. sediments). We focus on the Chad lineament, a 1300 km arcuate feature located between the west and central African rift system. The gravity fields show differences between the lineament and the west and central African rift system. Along the centre of the lineament high-density rocks must be present, which relate to either magmatic or metamorphic rocks. This is very different to the lineaments of the western and central-west African rift system which are filled with sediments. Considering present models of rifting and the absence of topography, the lineament cannot be coeval to the west and central African rift system and is most likely older. We suggest that the lineament is a structural element of the Saharan Metacraton.
New Palaeoproterozoic palaeomagnetic data from the Kaapvaal Craton, South Africa
Authors: Letts Shawn , Torsvik Trond H. , Webb Susan J. , Ashwal Lewis D.
Published: October 2011

Palaeomagnetic data from the well-dated 2060.6±0.5 Ma Phalaborwa Complex in South Africa (Kaapvaal Craton) are of excellent quality. High unblocking components are carried by magnetite and single polarity remanence directions (mean declination 5.0°, inclination 57.3°,
α
95
= 5.2°) yield a palaeomagnetic pole (latitude 27.7°N, longitude 35.8°E, A95 = 6.6°) that overlaps with existing poles from the near coeval 2054.4±1.3 Ma Bushveld Complex. The Phalaborwa and Bushveld complex poles, along with poles from the well-dated Vredefort impact (2023±4 Ma) and Post-Waterberg Dolerites (1874.6±3.9 Ma), define the most reliable poles for the Kaapvaal Craton during this time interval (
c.
2060–1875 Ma) and witness low rates of Mid-Palaeoproterozoic apparent polar wander. Poorly dated NE–NNE-trending dyke swarms that intrude the Phalaborwa and Bushveld complexes both yield dual-polarity remanence components that share a common mean at the 95% confidence level. Primary palaeomagnetic poles (Phalaborwa dykes pole latitude 7.6°, longitude 12.1°, A95 = 11.8°; Bushveld dykes pole latitude 12.6°, longitude 24.1°, A95 = 10.8°) suggest that they are of the same age as the Post-Waterberg dolerites (
c.
1875 Ma). They could also be as old as the Phalaborwa and Bushveld Complexes, however; high-precision geochronology is required to resolve this issue and to enlarge the number of Palaeoproterozoic key poles for the Kaapvaal Craton.
Polyphase Neoproterozoic orogenesis within the East Africa–Antarctica Orogenic Belt in central and northern Madagascar
Authors: Key R. M. , Pitfield P. E. J. , Thomas R. J. , Goodenough K. M. , De Waele B. , Schofield D. I. , Bauer W. , Horstwood M. S. A. , Styles M. T. , Conrad J. , Encarnacion J. , Lidke D. J. , O'Connor E. A. , Potter C. , Smith R. A. , Walsh G. J. , Ralison A. V. , Randriamananjara T. , Rafahatelo J.-M. , Rabarimanana M.
Published: October 2011

Our recent geological survey of the basement of central and northern Madagascar allowed us to re-evaluate the evolution of this part of the East Africa–Antarctica Orogen (EAAO). Five crustal domains are recognized, characterized by distinctive lithologies and histories of sedimentation, magmatism, deformation and metamorphism, and separated by tectonic and/or unconformable contacts. Four consist largely of Archaean metamorphic rocks (Antongil, Masora and Antananarivo Cratons, Tsaratanana Complex). The fifth (Bemarivo Belt) comprises Proterozoic meta-igneous rocks. The older rocks were intruded by plutonic suites at
c.
1000 Ma, 820–760 Ma, 630–595 Ma and 560–520 Ma. The evolution of the four Archaean domains and their boundaries remains contentious, with two end-member interpretations evaluated: (1) all five crustal domains are separate tectonic elements, juxtaposed along Neoproterozoic sutures and (2) the four Archaean domains are segments of an older Archaean craton, which was sutured against the Bemarivo Belt in the Neoproterozoic. Rodinia fragmented during the early Neoproterozoic with intracratonic rifts that sometimes developed into oceanic basins. Subsequent Mid-Neoproterozoic collision of smaller cratonic blocks was followed by renewed extension and magmatism. The global ‘Terminal Pan-African’ event (560–490 Ma) finally stitched together the Mid-Neoproterozoic cratons to form Gondwana.
HIV gene expression deactivates redox-sensitive stress response program in mouse tubular cells both in vitro and in vivo
Authors: Salhan Divya , Pathak Shresh , Husain Mohammad , Tandon Pranai , Kumar Dileep , Malhotra Ashwani , Meggs Leonard G. , Singhal Pravin C.
Published: October 2011

Human immunodeficiency virus (HIV)-1 has been reported to cause tubular cell injury both in in vivo and in vitro studies. In the present study, we evaluated the role of oxidative stress in the induction of apoptosis in HIV gene expressing mouse tubular cells in in vivo (Tg26, a transgenic mouse model of HIV-associated nephropathy) and in vitro (tubular cells were transduced with pNL4-3: ΔG/P-GFP, VSV.G psueudo typed virus) studies. Although Tg26 mice showed enhanced tubular cell reactive oxygen species (ROS) generation and apoptosis, renal tissue did not display a robust antioxidant response in the form of enhanced free radical scavenger (MnSOD/catalase) expression. Tg26 mice not only showed enhanced tubular cell expression of phospho-p66ShcA but also displayed nuclear Foxo3a translocation to the cytoplasm. These findings indicated deactivation of tubular cell Foxo3A-dependent redox-sensitive stress response program (RSSRP) in Tg26 mice. In in vitro studies, NL4-3 (pNL4-3: ΔG/P-GFP, VSV.G pseudotyped virus)-transduced mouse proximal tubular cells (NL4-3/MPTEC) displayed enhanced phosphorylation of p66ShcA. NL4-3/MPTECs also displayed greater ( P < 0.01) ROS generation when compared with empty vector-transduced tubular cells; however, both diminution of p66ShcA and N-acetyl cysteine attenuated NL4-3-induced tubular cell ROS generation as well as apoptosis. In addition, both antioxidants and free radical scavengers partially inhibited HIV-induced tubular cell apoptosis. NL4-3/MPTEC displayed deactivation of RSSRP in the form of enhanced phosphorylation of Foxo3A and attenuated expression of superoxide dismutase (SOD) and catalase. Since both SOD and catalase were able to provide protection against HIV-1-induced tubular cell apoptosis, it suggests that HIV-1-induced proapoptotic effect may be a consequence of the deactivated RSSRP.
IL-17A stimulates granulocyte colony-stimulating factor production via ERK1/2 but not p38 or JNK in human renal proximal tubular epithelial cells
Authors: Hirai Yuki , Iyoda Masayuki , Shibata Takanori , Kuno Yoshihiro , Kawaguchi Mio , Hizawa Nobuyuki , Matsumoto Kei , Wada Yukihiro , Kokubu Fumio , Akizawa Tadao
Published: October 2011

We investigated the potential role of IL-17A in the induction of granulocyte colony-stimulating factor (G-CSF), a critical granulopoietic growth factor, in human renal proximal tubular epithelial cells. Human renal proximal tubular cells (HK-2, ATCC) were used to characterize the effects of IL-17A or IL-17F on G-CSF production, using ELISA, real-time RT-PCR, and immunoblotting. The cell surface expression of IL-17 receptors (IL-17Rs) was analyzed by flow cytometry. IL-17A stimulation of proximal tubular cells led to a dose- and time-dependent increase in secreted G-CSF. This effect was dependent on mRNA transcription and protein translation. Real-time RT-PCR demonstrated that G-CSF mRNA expression reached a maximum level at 6 h following IL-17A stimulation and that this increase was dose dependent. Both IL-17RA and IL-17RC were expressed on proximal tubular cells. IL-17A also enhanced TNF-α- or IL-1β-mediated G-CSF secretion from cells. Additionally, IL-17A induced MAPK (ERK1/2 but not p38 MAPK or JNK) activation, and pharmacological inhibitors of MEK1/2 (U0126) but not of p38 MAPK (SB203580) or JNK (SP600125), significantly blocked the IL-17A-mediated G-CSF release. We demonstrated the potential ability of IL-17A to induce G-CSF in renal proximal tubular cells. It is proposed that IL-17A may play an important role in neutrophil transmigration and activation via stimulation of G-CSF in tubular injury.
Renal functional responses to selective intrarenal renin inhibition in Cyp1a1-Ren2 transgenic rats with ANG II-dependent malignant hypertension
Authors: Howard Catherine G. , Mitchell Kenneth D.
Published: October 2011

Angiotensin (ANG) II-dependent hypertension is characterized by increases in intrarenal ANG II levels, derangement in renal hemodynamics, and augmented tubular sodium reabsorptive capability. Increased nephron expression of renin-angiotensin system components, such as angiotensinogen by proximal tubule cells and renin by collecting duct principal cells, has been associated with an augmented ability of the kidney to form ANG II in hypertensive states. However, the contribution of de novo intrarenal ANG II production to the development and maintenance of ANG II-dependent hypertension remains unclear. The present study was performed to determine the effects of selective intrarenal renin inhibition on whole kidney hemodynamics and renal excretory function in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension in the absence of the confounding influence of associated reductions in mean arterial pressure (MAP). Male Cyp1a1-Ren2 transgenic rats were induced to develop malignant hypertension, anesthetized, and surgically prepared for intrarenal administration of the direct renin inhibitor aliskiren (0.01 mg/kg). Following acute aliskiren treatment, urine flow and sodium excretion increased (10.5 ± 1.1 to 15.9 ± 1.9 μl/min, P < 0.001; 550 ± 160 to 1,370 ± 320 neq/min, P < 0.001, respectively) and ANG II excretion decreased (120 ± 30 to 63 ± 17 fmol/h, P < 0.05). There were no significant changes in MAP, glomerular filtration rate, estimated renal plasma flow, plasma ANG II levels, or protein excretion. The present findings demonstrate that selective renal renin inhibition elicits diuretic and natriuretic responses in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension. Elevated intraluminal ANG II levels likely act to augment tubular reabsorptive function and, thereby, contribute to the elevated blood pressure in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension.
TMPRSS4-dependent activation of the epithelial sodium channel requires cleavage of the γ-subunit distal to the furin cleavage site
Authors: Passero Christopher J. , Mueller Gunhild M. , Myerburg Michael M. , Carattino Marcelo D. , Hughey Rebecca P. , Kleyman Thomas R.
Published: October 2011

The epithelial sodium channel (ENaC) is activated by a unique mechanism, whereby inhibitory tracts are released by proteolytic cleavage within the extracellular loops of two of its three homologous subunits. While cleavage by furin within the biosynthetic pathway releases one inhibitory tract from the α-subunit and moderately activates the channel, full activation through release of a second inhibitory tract from the γ-subunit requires cleavage once by furin and then at a distal site by a second protease, such as prostasin, plasmin, or elastase. We now report that coexpression of mouse transmembrane protease serine 4 (TMPRSS4) with mouse ENaC in Xenopus oocytes was associated with a two- to threefold increase in channel activity and production of a unique ∼70-kDa carboxyl-terminal fragment of the γ-subunit, similar to the ∼70-kDa γ-subunit fragment that we previously observed with prostasin-dependent channel activation. TMPRSS4-dependent channel activation and production of the ∼70-kDa fragment were partially blocked by mutation of the prostasin-dependent cleavage site (γRKRK186QQQQ). Complete inhibition of TMPRSS4-dependent activation of ENaC and γ-subunit cleavage was observed when three basic residues between the furin and prostasin cleavage sites were mutated (γK173Q, γK175Q, and γR177Q), in addition to γRKRK186QQQQ. Mutation of the four basic residues associated with the furin cleavage site (γRKRR143QQQQ) also prevented TMPRSS4-dependent channel activation. We conclude that TMPRSS4 primarily activates ENaC by cleaving basic residues within the tract γK173-K186 distal to the furin cleavage site, thereby releasing a previously defined key inhibitory tract encompassing γR158-F168 from the γ-subunit.
17β-Estradiol induces nongenomic effects in renal intercalated cells through G protein-coupled estrogen receptor 1
Authors: Hofmeister Marlene Vind , Damkier Helle Hasager , Christensen Birgitte Mønster , Olde Björn , Fredrik Leeb-Lundberg L. M. , Fenton Robert A. , Praetorius Helle A. , Praetorius Jeppe
Published: October 2011

Steroid hormones such as 17β-estradiol (E2) are known to modulate ion transporter expression in the kidney through classic intracellular receptors. Steroid hormones are also known to cause rapid nongenomic responses in a variety of nonrenal tissues. However, little is known about renal short-term effects of steroid hormones. Here, we studied the acute actions of E2 on intracellular Ca2+signaling in isolated distal convoluted tubules (DCT2), connecting tubules (CNT), and initial cortical collecting ducts (iCCD) by fluo 4 fluorometry. Physiological concentrations of E2 induced transient increases in intracellular Ca2+concentration ([Ca2+]i) in a subpopulation of cells. The [Ca2+]iincreases required extracellular Ca2+and were inhibited by Gd3+. Strikingly, the classic E2 receptor antagonist ICI 182,780 also increased [Ca2+]i, which is inconsistent with the activation of classic E2 receptors. G protein-coupled estrogen receptor 1 (GPER1 or GPR30) was detected in microdissected DCT2/CNT/iCCD by RT-PCR. Stimulation with the specific GPER1 agonist G-1 induced similar [Ca2+]iincreases as E2, and in tubules from GPER1 knockout mice, E2, G-1, and ICI 182,780 failed to induce [Ca2+]ielevations. The intercalated cells showed both E2-induced concanamycin-sensitive H+-ATPase activity by BCECF fluorometry and the E2-mediated [Ca2+]iincrement. We propose that E2 via GPER1 evokes [Ca2+]itransients and increases H+-ATPase activity in intercalated cells in mouse DCT2/CNT/iCCD.
Modeling stochastic and spatial heterogeneity in a human airway tree to determine variation in respiratory system resistance
Authors: Leary Del , Bhatawadekar Swati A. , Parraga Grace , Maksym Geoffrey N.
Published: October 2011

Asthma is a variable disease with changes in symptoms and airway function over many time scales. Airway resistance ( Raw) is variable and thought to reflect changes in airway smooth muscle activity, but just how variation throughout the airway tree and the influence of gas distribution abnormalities affect Raw is unclear. We used a multibranch airway lung model to evaluate variation in airway diameter size, the role of coherent regional variation, and the role of gas distribution abnormalities on mean Raw ( R̄aw) and variation in Raw as described by the SD ( SDRaw). We modified an anatomically correct airway tree, provided by Merryn Tawhai (The University of Auckland, New Zealand), consisting of nearly 4,000 airways, to produce temporal and spatial heterogeneity. As expected, we found that increasing the diameter variation by twofold, with no change in the mean diameter, increased SDRaw more than fourfold. Perhaps surprisingly, R̄aw was proportional to SDRaw under several conditions—when either mean diameter was fixed, and its SD varied or when mean diameter varied, and SD was fixed. Increasing the size of a regional absence in gas distribution (ventilation defect) also led to a proportionate increase in both R̄aw and SDRaw. However, introducing regional dependence of connected airways strongly increased SDRaw by as much as sixfold, with little change in R̄aw. The model was able to predict previously reported Raw distributions and correlation of SDRaw on Raw in healthy and asthmatic subjects. The ratio of SDRaw to R̄aw depended most strongly on interairway coherent variation and only had a slight dependence on ventilation defect size. These findings may explain the linear correlation between variation and mean values of Raw but also suggest that regional alterations in gas distribution and local coordination in ventilation amplify any underlying variation in airway diameters throughout the airway tree.
Evidence for active control of perfusion within lung microvessels
Authors: Watson Kal E. , Dovi William F. , Conhaim Robert L.
Published: October 2011

Vasoconstrictors cause contraction of pulmonary microvascular endothelial cells in culture. We wondered if this meant that contraction of these cells in situ caused active control of microvascular perfusion. If true, it would mean that pulmonary microvessels were not simply passive tubes and that control of pulmonary microvascular perfusion was not mainly due to the contraction and dilation of arterioles. To test this idea, we vasoconstricted isolated perfused rat lungs with angiotensin II, bradykinin, serotonin, or U46619 (a thromboxane analog) at concentrations that produced equal flows. We also perfused matched-flow controls. We then infused a bolus of 3 μm diameter particles into each lung and measured the rate of appearance of the particles in the venous effluent. We also measured microscopic trapping patterns of particles retained within each lung. Thirty seconds after particle infusion, venous particle concentrations were significantly lower ( P ≤ 0.05) for lungs perfused with angiotensin II or bradykinin than for those perfused with U46619, but not significantly different from serotonin perfused lungs or matched flow controls. Microscopic clustering of particles retained within the lungs was significantly greater ( P ≤ 0.05) for lungs perfused with angiotensin II, bradykinin, or serotonin, than for lungs perfused with U46619 or for matched flow controls. Our results suggest that these agents did not produce vasoconstriction by a common mechanism and support the idea that pulmonary microvessels possess a level of active control and are not simply passive exchange vessels.
Resistance exercise training improves age-related declines in leg vascular conductance and rejuvenates acute leg blood flow responses to feeding and exercise
Authors: Phillips Bethan , Williams John , Atherton Philip , Smith Kenneth , Hildebrandt Wulf , Rankin Debbie , Greenhaff Paul , Macdonald Ian , Rennie Michael J.
Published: October 2011

One manifestation of age-related declines in vascular function is reduced peripheral (limb) blood flow and vascular conduction at rest and in response to vasodilatory stimuli such as exercise and feeding. Since, even in older age, resistance exercise training (RET) represents an efficacious strategy for increasing muscle mass and function, we hypothesized that likewise RET would improve age-related declines in leg blood flow (LBF) and vascular conductance (LVC). We studied three mixed-sex age groups (young: 18–28 yr, n = 14; middle aged: 45–55 yr, n = 20; older: 65–75 yr, n = 17) before and after 20 wk of whole body RET in the postabsorptive state (BASAL) and after unilateral leg extensions (6 × 8 repetitions; 75% 1 repetition maximum) followed by intermittent mixed-nutrient liquid feeds (∼6.5 kJ·kg−1·30 min−1), which allowed us to discern the acute effects of feeding (nonexercised leg; FED) and exercise plus feeding (exercised leg; FEDEX) on vascular function. We measured LBF using Doppler ultrasound and recorded mean arterial pressure (MAP) to calculate LVC. Our results reveal that although neither age nor RET influenced BASAL LBF, age-related declines in LBF responses to FED were eradicated by RET. Moreover, increases in LBF after FEDEX, which occurred only in young and middle-aged groups before RET (+73 ± 9%, and +90 ± 13%, P < 0.001, respectively), increased in all groups after RET (young +78 ± 10%, middle-aged +96 ± 15%, older +80 ± 19%, P < 0.001). Finally, RET robustly improved LVC under FASTED, FED, and FEDEX conditions in the older group. These data provide novel information that supports the premise that RET represents a valuable strategy to counter age-related impairments in LBF/LVC.
Knockout of glial channel ACD-1 exacerbates sensory deficits in aC. elegansmutant by regulating calcium levels of sensory neurons
Authors: Wang Ying , D'Urso Giulia , Bianchi Laura
Published: October 2011

Degenerin/epithelial Na+channels (DEG/ENaCs) are voltage-independent Na+or Na+/Ca2+channels expressed in many tissues and are needed for a wide range of physiological functions, including sensory perception and transepithelial Na+transport. In the nervous system, DEG/ENaCs are expressed in both neurons and glia. However, the role of glial vs. neuronal DEG/ENaCs remains unclear. We recently reported the characterization of a novel DEG/ENaC in Caenorhabditis elegans that we named ACD-1. ACD-1 is expressed in glial amphid sheath cells. The glial ACD-1, together with the neuronal DEG/ENaC DEG-1, is necessary for acid avoidance and attraction to lysine. We report presently that knockout of acd-1 in glia exacerbates sensory deficits caused by another mutant: the hypomorphic allele of the cGMP-gated channel subunit tax-2. Furthermore, sensory deficits caused by mutations in Giprotein odr-3 and guanylate cyclase daf-11, which regulate the activity of TAX-2/TAX-4 channels, are worsened by knockout of acd-1. We also show that sensory neurons of acd-1 tax-2(p694) double mutants fail to undergo changes in intracellular Ca2+when animals are exposed to low concentrations of attractant. Finally, we show that exogenous expression of TRPV1 in sensory neurons and exposure to capsaicin rescue sensory deficits of acd-1 tax-2(p694) mutants, suggesting that sensory deficits of these mutants are bypassed by increasing neuronal excitability. Our data suggest a role of glial DEG/ENaC channel ACD-1 in supporting neuronal activity.
Cross-validated models of the relationships between neck muscle electromyography and three-dimensional head kinematics during gaze behavior
Authors: Farshadmanesh Farshad , Byrne Patrick , Keith Gerald P. , Wang Hongying , Corneil Brian D. , Crawford J. Douglas
Published: October 2011

The object of this study was to model the relationship between neck electromyography (EMG) and three-dimensional (3-D) head kinematics during gaze behavior. In two monkeys, we recorded 3-D gaze, head orientation, and bilateral EMG activity in the sternocleidomastoid, splenius capitis, complexus, biventer cervicis, rectus capitis posterior major, and occipital capitis inferior muscles. Head-unrestrained animals fixated and made gaze saccades between targets within a 60° × 60° grid. We performed a stepwise regression in which polynomial model terms were retained/rejected based on their tendency to increase/decrease a cross-validation-based measure of model generalizability. This revealed several results that could not have been predicted from knowledge of musculoskeletal anatomy. During head holding, EMG activity in most muscles was related to horizontal head orientation, whereas fewer muscles correlated to vertical head orientation and none to small random variations in head torsion. A fourth-order polynomial model, with horizontal head orientation as the only independent variable, generalized nearly as well as higher order models. For head movements, we added time-varying linear and nonlinear perturbations in velocity and acceleration to the previously derived static (head holding) models. The static models still explained most of the EMG variance, but the additional motion terms, which included horizontal, vertical, and torsional contributions, significantly improved the results. Several coordinate systems were used for both static and dynamic analyses, with Fick coordinates showing a marginal (nonsignificant) advantage. Thus, during gaze fixations, recruitment within the neck muscles from which we recorded contributed primarily to position-dependent horizontal orientation terms in our data set, with more complex multidimensional contributions emerging during the head movements that accompany gaze shifts. These are crucial components of the late neuromuscular transformations in a complete model of 3-D head-neck system and should help constrain the study of premotor signals for head control during gaze behaviors.
Neuromodulation independently determines correlated channel expression and conductance levels in motor neurons of the stomatogastric ganglion
Authors: Temporal Simone , Desai Mohati , Khorkova Olga , Varghese Gladis , Dai Aihua , Schulz David J. , Golowasch Jorge
Published: October 2011

Neuronal identity depends on the regulated expression of numerous molecular components, especially ionic channels, which determine the electrical signature of a neuron. Such regulation depends on at least two key factors, activity itself and neuromodulatory input. Neuronal electrical activity can modify the expression of ionic currents in homeostatic or nonhomeostatic fashion. Neuromodulators typically modify activity by regulating the properties or expression levels of subsets of ionic channels. In the stomatogastric system of crustaceans, both types of regulation have been demonstrated. Furthermore, the regulation of the coordinated expression of ionic currents and the channels that carry these currents has been recently reported in diverse neuronal systems, with neuromodulators not only controlling the absolute levels of ionic current expression but also, over long periods of time, appearing to modify their correlated expression. We hypothesize that neuromodulators may regulate the correlated expression of ion channels at multiple levels and in a cell-type-dependent fashion. We report that in two identified neuronal types, three ionic currents are linearly correlated in a pairwise manner, suggesting their coexpression or direct interactions, under normal neuromodulatory conditions. In each cell, some currents remain correlated after neuromodulatory input is removed, whereas the correlations between the other pairs are either lost or altered. Interestingly, in each cell, a different suite of currents change their correlation. At the transcript level we observe distinct alterations in correlations between channel mRNA amounts, including one of the cell types lacking a correlation under normal neuromodulatory conditions and then gaining the correlation when neuromodulators are removed. Synaptic activity does not appear to contribute, with one possible exception, to the correlated expression of either ionic currents or of the transcripts that code for the respective channels. We conclude that neuromodulators regulate the correlated expression of ion channels at both the transcript and the protein levels.
In vivo responses of cutaneous C-mechanosensitive neurons in mouse to punctate chemical stimuli that elicit itch and nociceptive sensations in humans
Authors: Ma C. , Nie H. , Gu Q. , Sikand P. , LaMotte R. H.
Published: October 2011

Native cowhage spicules, and heat-inactivated spicules containing histamine or capsaicin, evoke similar sensations of itch and nociceptive sensations in humans. In ongoing studies of the peripheral neural mechanisms of chemical itch and pain in the mouse, extracellular electrophysiological recordings were obtained, in vivo, from the cell bodies of mechanosensitive nociceptive neurons in response to spicule stimuli delivered to their cutaneous receptive fields (RFs) on the distal hindlimb. A total of 43 mechanosensitive, cutaneous, nociceptive neurons with axonal conduction velocities in the C-fiber range (C-nociceptors) were classified as CM if responsive to noxious mechanical stimuli, such as pinch, or CMH if responsive to noxious mechanical and heat stimuli (51°C, 5 s). The tips of native cowhage spicules, or heat-inactivated spicules containing histamine or capsaicin, were applied to the RF. Heat-inactivated spicules containing no chemical produced only a transient response occurring during insertion. Of the 43 mechanosensitive nociceptors recorded, 20 of the 25 CMHs responded to capsaicin, and of these, 13 also responded to cowhage and/or histamine. In contrast, none of the 18 CMs responded to any of the chemical stimuli. The time course of the mean discharge rate of CMHs was similar in response to each type of spicule and generally similar, although reaching a peak earlier, to the temporal profiles of itch and nociceptive sensations evoked by the same stimuli in humans. These findings are consistent with the hypothesis that the itch and nociceptive sensations evoked by these punctuate chemical stimuli are mediated at least in part by the activity of mechanoheat-sensitive C-nociceptors. In contrast, activity in mechanosensitive C-nociceptors that do not respond to heat or to pruritic chemicals is hypothesized as contributing to pain but not to itch.
Central chemoreceptor modulation of breathing via multipath tuning in medullary ventrolateral respiratory column circuits
Authors: Ott Mackenzie M. , Nuding Sarah C. , Segers Lauren S. , O'Connor Russell , Morris Kendall F. , Lindsey Bruce G.
Published: October 2011

Ventrolateral respiratory column (VRC) circuits that modulate breathing in response to changes in central chemoreceptor drive are incompletely understood. We employed multielectrode arrays and spike train correlation methods to test predictions of the hypothesis that pre-Bötzinger complex (pre-BötC) and retrotrapezoid nucleus/parafacial (RTN-pF) circuits cooperate in chemoreceptor-evoked tuning of ventral respiratory group (VRG) inspiratory neurons. Central chemoreceptors were selectively stimulated by injections of CO2-saturated saline into the vertebral artery in seven decerebrate, vagotomized, neuromuscularly blocked, and artificially ventilated cats. Among sampled neurons in the Bötzinger complex (BötC)-to-VRG region, 70% (161 of 231) had a significant change in firing rate after chemoreceptor stimulation, as did 70% (101 of 144) of the RTN-pF neurons. Other responsive neurons (24 BötC-VRG; 11 RTN-pF) had a change in the depth of respiratory modulation without a significant change in average firing rate. Seventy BötC-VRG chemoresponsive neurons triggered 189 offset-feature correlograms (96 peaks; 93 troughs) with at least one responsive BötC-VRG cell. Functional input from at least one RTN-pF cell could be inferred for 45 BötC-VRG neurons (19%). Eleven RTN-pF cells were correlated with more than one BötC-VRG target neuron, providing evidence for divergent connectivity. Thirty-seven RTN-pF neurons, 24 of which were chemoresponsive, were correlated with at least one chemoresponsive BötC-VRG neuron. Correlation linkage maps and spike-triggered averages of phrenic nerve signals suggest transmission of chemoreceptor drive via a multipath network architecture: RTN-pF modulation of pre-BötC-VRG rostral-to-caudal excitatory inspiratory neuron chains is tuned by feedforward and recurrent inhibition from other inspiratory neurons and from “tonic” expiratory neurons.