bluuebunny/crossref_metadata_2025 huggingface dataset:
Arsenic Trioxide Stabilizes Accumulations of Adeno-Associated Virus Virions at the Perinuclear Region, Increasing Transduction
In Vitro
and
In Vivo
Authors: Mitchell Angela M. , Li Chengwen , Samulski R. Jude
Published: February 2013

Interactions with cellular stress pathways are central to the life cycle of many latent viruses. Here, we utilize adeno-associated virus (AAV) as a model to study these interactions, as previous studies have demonstrated that cellular stressors frequently increase transduction of recombinant AAV (rAAV) vectors and may even substitute for helper virus functions. Since several chemotherapeutic drugs are known to increase rAAV transduction, we investigated the effect of arsenic trioxide (As
2
O
3
), an FDA-approved chemotherapeutic agent with known effects on several other virus life cycles, on the transduction of rAAV.
In vitro
, As
2
O
3
caused a dose-dependent increase in rAAV2 transduction over a broad range of cell lines from various cell types and species (e.g., HEK-293, HeLa, HFF hTERT, C-12, and Cos-1). Mechanistically, As
2
O
3
treatment acted to prevent loss of virions from the perinuclear region, which correlated with increased cellular vector genome retention, and was distinguishable from proteasome inhibition. To extend our investigation of the cellular mechanism, we inhibited reactive oxygen species formation and determined that the As
2
O
3
-mediated increase in rAAV2 transduction was dependent upon production of reactive oxygen species. To further validate our
in vitro
data, we tested the effect of As
2
O
3
on rAAV transduction
in vivo
and determined that treatment initiated transgene expression as early as 2 days posttransduction and increased reporter expression by up to 10-fold. Moreover, the transduction of several other serotypes of rAAV was also enhanced
in vivo
, suggesting that As
2
O
3
affects a pathway used by several AAV serotypes. In summary, our data support a model wherein As
2
O
3
increases rAAV transduction both
in vitro
and
in vivo
and maintains perinuclear accumulations of capsids, facilitating productive nuclear trafficking.
A Doubly Fluorescent HIV-1 Reporter Shows that the Majority of Integrated HIV-1 Is Latent Shortly after Infection
Authors: Dahabieh Matthew S. , Ooms Marcel , Simon Viviana , Sadowski Ivan
Published: February 2013

HIV-1 latency poses a major barrier to viral eradication. Canonically, latency is thought to arise from progressive epigenetic silencing of active infections. However, little is known about when and how long terminal repeat (LTR)-silent infections arise since the majority of the current latency models cannot differentiate between initial (LTR-silent) and secondary (progressive silencing) latency. In this study, we constructed and characterized a novel, double-labeled HIV-1 vector (Red-Green-HIV-1 [RGH]) that allows for detection of infected cells independently of LTR activity. Infection of Jurkat T cells and other cell lines with RGH suggests that the majority of integrated proviruses were LTR-silent early postinfection. Furthermore, the LTR-silent infections were transcriptionally competent, as the proviruses could be reactivated by a variety of T cell signaling agonists. Moreover, we used the double-labeled vector system to compare LTRs from seven different subtypes with respect to LTR silencing and reactivation. These experiments indicated that subtype D and F LTRs were more sensitive to silencing, whereas the subtype AE LTR was largely insensitive. Lastly, infection of activated human primary CD4+T cells yielded LTR-silent as well as productive infections. Taken together, our data, generated using the newly developed RGH vector as a sensitive tool to analyze HIV-1 latency on a single-cell level, show that the majority of HIV-1 infections are latent early postinfection.
Adaptive Immune Responses Elicited by Baculovirus and Impacts on Subsequent Transgene Expression
In Vivo
Authors: Luo Wen-Yi , Lin Shih-Yeh , Lo Kai-Wei , Lu Chia-Hsin , Hung Chang-Lin , Chen Chi-Yuan , Chang Chien-Chung , Hu Yu-Chen
Published: February 2013

Baculovirus (BV) is a promising gene therapy vector and typically requires readministration because BV mediates transient expression. However, how the prime-boost regimen triggers BV-specific adaptive responses and their impacts on BV readministration, transgene expression, and therapeutic/vaccine efficacy remain unknown. Here we unraveled that BV injection into BALB/c mice induced the production of BV-specific antibodies, including IgG1 and IgG2a, which could neutralize BV by antagonizing the envelope protein gp64 and impede BV-mediated transgene expression. Moreover, humans did not possess preexisting anti-BV antibodies. BV injection also elicited BV-specific Th1 and Th2 responses as well as CD4
+
and CD8
+
T cell responses. gp64 was a primary immunogen to activate the antibody and CD8
+
T cell response, with its peptide at positions 457 to 465 (peptide 457-465) being the major histocompatibility complex (MHC) class I epitope to stimulate CD8
+
T cell and cytotoxic responses. Nonetheless, a hybrid
Sleeping Beauty
-based BV enabled long-term expression for >1 year by a single injection, indicating that the T cell responses did not completely eradicate BV-transduced cells and implicating the potential of this hybrid BV vector for gene therapy. These data unveil that BV injection triggers adaptive immunity and benefit rational design of BV administration schemes for gene therapy and vaccination.
Roles Played by Capsid-Dependent Induction of Membrane Curvature and Gag-ESCRT Interactions in Tetherin Recruitment to HIV-1 Assembly Sites
Authors: Grover Jonathan R. , Llewellyn G. Nicholas , Soheilian Ferri , Nagashima Kunio , Veatch Sarah L. , Ono Akira
Published: February 2013

Tetherin/BST-2 (here called tetherin) is an antiviral protein that restricts release of diverse enveloped viruses from infected cells through physically tethering virus envelope and host plasma membrane. For HIV-1, specific recruitment of tetherin to assembly sites has been observed as its colocalization with the viral structural protein Gag or its accumulation in virus particles. Because of its broad range of targets, we hypothesized that tetherin is recruited through conserved features shared among various enveloped viruses, such as lipid raft association, membrane curvature, or ESCRT dependence. We observed that reduction of cellular cholesterol does not block tetherin anti-HIV-1 function, excluding an essential role for lipid rafts. In contrast, mutations in the capsid domain of Gag, which inhibit induction of membrane curvature, prevented tetherin-Gag colocalization detectable by confocal microscopy. Disruption of Gag-ESCRT interactions also inhibited tetherin-Gag colocalization when disruption was accomplished via amino acid substitutions in late domain motifs, expression of a dominant-negative Tsg101 derivative, or small interfering RNA (siRNA)-mediated depletion of Tsg101 or Alix. However, further analyses of these conditions by quantitative superresolution localization microscopy revealed that Gag-tetherin coclustering is significantly reduced but persists at intermediate levels. Notably, this residual tetherin recruitment was still sufficient for the full restriction of HIV-1 release. Unlike the late domain mutants, the capsid mutants defective in inducing membrane curvature showed little or no coclustering with tetherin in superresolution analyses. These results support a model in which both Gag-induced membrane curvature and Gag-ESCRT interactions promote tetherin recruitment, but the recruitment level achieved by the former is sufficient for full restriction.
Hepatitis-associated aplastic anaemia: a poor prognosis
Authors: Gonçalves Vivian , Calado Rita , Palaré Maria João , Ferrão Anabela , Morais Anabela
Published: February 2013

A 13-year-old boy presented with spontaneous skin and mucosal bleeds 3 weeks after acute hepatitis of unknown aetiology. Laboratory analyses revealed pancytopenia and bone marrow biopsy that confirmed the diagnosis of aplastic anaemia. Other causes of congenital and acquired aplastic anaemia were excluded. He was diagnosed with hepatitis-associated aplastic anaemia. He developed a critical clinical condition, becoming totally dependent on erythrocyte and platelet transfusions, and severe neutropenia, which led to invasive bacterial infection. He died due to sepsis with multiple organ failure 3 months after admission.
A rare case of dengue encephalitis
Authors: Rao Sachin , Kumar Manish , Ghosh Soumik , Gadpayle Adesh Kumar
Published: February 2013

Dengue fever has a variable clinical spectrum ranging from asymptomatic infection to life-threatening dengue haemorrhagic fever and dengue shock syndrome. However, neurological complications, in general, are unusual. Dengue encephalopathy is not an unknown entity; however, dengue encephalitis, a direct neuronal infiltration by the dengue virus, is an extremely rare disease. Although dengue is classically considered a non-neurotropic virus, there is increasing evidence for dengue viral neurotropism, suggesting that, in a proportion of cases, there may be an element of direct viral encephalitis. An MRI brain rarely shows focal abnormalities in dengue encephalitis. We report an interesting case of dengue encephalitis during an outbreak in Delhi, India. The diagnosis was confirmed by blood and cerebrospinal fluid dengue serology and (NS1) antigen assay. The case showed extensive lesions involving the midbrain, cerebellum, thalamus and medial temporal region on both sides of the MRI brain, which is an uncommon manifestation of dengue fever.
Impact of route to diagnosis on treatment intent and 1-year survival in patients diagnosed with oesophagogastric cancer in England: a prospective cohort study
Authors: Palser Thomas R , Cromwell David A , Hardwick Richard H , Riley Stuart A , Greenaway Kimberley , van der Meulen Jan H P
Published: February 2013

Objective

To investigate the relationship between the route to diagnosis, patient characteristics, treatment intent and 1 -year survival among patients with oesophagogastric (O-G) cancer.

Setting

Cohort study in 142 English NHS trusts and 30 cancer networks.

Participants

Patients diagnosed with O-G cancer between October 2007 and June 2009.

Design

Prospective cohort study. Route to diagnosis defined as general practitioner (GP) referral—urgent (suspected cancer) or non-urgent, hospital consultant referral, or after an emergency admission. Logistic regression was used to estimate associations and adjust for differences in casemix.

Main outcome measures

Proportion of patients diagnosed by route of diagnosis; proportion of patients selected for curative treatment; 1-year survival.

Results

Among 14 102 cancer patients, 66.3% were diagnosed after a GP referral, 16.4% after an emergency admission and 17.4% after a hospital consultant referral. Of the 9351 GP referrals, 68.8% were urgent. Compared to urgent GP referrals, a markedly lower proportion of patients diagnosed after emergency admission had a curative treatment plan (36% vs 16%; adjusted OR=0.62, 95% CI 0.52 to 0.74) and a lower proportion survived 1 year (43% vs 27%; OR 0.78; 95% CI 0.68 to 0.89). Urgency of GP referral did not affect treatment intent or survival. Routes to diagnosis varied across cancer networks, with the adjusted proportion of patients diagnosed after emergency admission ranging from 8.7 to 32.3%.

Conclusions

Outcomes for cancer patients are worse if diagnosed after emergency admission. Primary care and hospital services should work together to reduce rates of diagnosis after emergency admission and the variation across cancer networks.
Randomised comparison of the effectiveness of the laryngeal mask airway supreme, i-gel and current practice in the initial airway management of prehospital cardiac arrest (REVIVE-Airways): a feasibility study research protocol
Authors: Benger Jonathan Richard , Voss Sarah , Coates David , Greenwood Rosemary , Nolan Jerry , Rawstorne Steven , Rhys Megan , Thomas Matthew
Published: February 2013

Introduction

Effective cardiopulmonary resuscitation with appropriate airway management improves outcomes following out-of-hospital cardiac arrest (OHCA). Historically, tracheal intubation has been accepted as the optimal form of OHCA airway management in the UK. The Joint Royal Colleges Ambulance Liaison Committee recently concluded that newer supraglottic airway devices (SADs) are safe and effective devices for hospital procedures and that their use in OHCA should be investigated. This study will address an identified gap in current knowledge by assessing whether it is feasible to use a cluster randomised design to compare SADs with current practice, and also to each other, during OHCA.

Methods and analysis

The primary objective of this study is to assess the feasibility of a cluster randomised trial to compare the ventilation success of two newer SADs: the i-gel and the laryngeal mask airway supreme to usual practice during the initial airway management of OHCA. The secondary objectives are to collect data on ventilation success, further airway interventions required, loss of a previously established airway during transport, airway management on arrival at hospital (or termination of the resuscitation attempt), initial resuscitation success, survival to intensive care admission, survival to hospital discharge and patient outcome at 3 months. Ambulance paramedics will be randomly allocated to one of the three methods of airway management. Adults in medical OHCA attended by a trial paramedic will be eligible for the study.

Ethics and dissemination

Approval for the study has been obtained from a National Health Service Research Ethics Committee with authority to review proposals for trials of a medical device in incapacitated adults. The results will be made publicly available on an open access website, and we will publish the findings in appropriate journals and present them at national and international conferences relevant to the subject field.

Trial registration

ISRCTN: 18528625.
Reduced overtriage and undertriage with a new triage system in an urban accident and emergency department in Botswana: a cohort study
Authors: Mullan Paul C , Torrey Susan B , Chandra Amit , Caruso Ngaire , Kestler Andrew
Published: February 2013

Background

Improvements in triage have demonstrated improved clinical outcomes in resource-limited settings. In 2009, the Accident and Emergency (A&E) Department at the Princess Marina Hospital (PMH) in Botswana identified the need for a more objective triage system and adapted the South African Triage Scale to create the PMH A&E Triage Scale (PATS).

Aim

The primary purpose was to compare the undertriage and overtriage rates in the PATS and pre-PATS study periods.

Methods

Data were collected from 5 April 2010 to 1 May 2011 for the PATS and compared with a database of patients triaged from 1 October 2009 to 24 March 2010 for the pre-PATS. Data included patient disposition outcomes, demographics and triage level assignments.

Results

14 706 (pre-PATS) and 25 243 (PATS) patient visits were reviewed. Overall, overtriage rates improved from 53% (pre-PATS) to 38% (PATS) (p<0.001); likewise, undertriage rates improved from 47% (pre-PATS) to 16% (PATS) (p<0.001). Statistically significant decreases in both rates were found when paediatric and adult cases were analysed separately. PATS was more predictive of inpatient admission, Intensive Care Unit (ICU) admission and death rates in the A&E than was the pre-PATS. The lowest acuity category of each system had a 0.6% (pre-PATS) and 0% (PATS) chance of death in the A&E or ICU admission (p<0.001). No change in death rate was seen between the pre-PATS and PATS, but ICU admission rates decreased from 0.35% to 0.06% (p<0.001).

Conclusions

PATS is a more predictive triage system than pre-PATS as evidenced by improved overtriage, undertriage and patient severity predictability across triage levels.
Pulsatility in CSF dynamics: pathophysiology of idiopathic normal pressure hydrocephalus
Authors: Qvarlander Sara , Lundkvist Bo , Koskinen Lars-Owe D , Malm Jan , Eklund Anders
Published: February 2013

Background

It is suggested that disturbed CSF dynamics are involved in the pathophysiology of idiopathic normal pressure hydrocephalus (INPH). The pulsatility curve describes the relationship between intracranial pressure (ICP) and the amplitude of cardiac related ICP pulsations. The position of baseline ICP on the curve provides information about the physiological state of the CSF dynamic system. The objective of the study was to investigate if shunt surgery modifies the pulsatility curve and the baseline position on the curve, and how this relates to gait improvement in INPH.

Methods

51 INPH patients were investigated with lumbar CSF dynamic investigations preoperatively and 5 months after shunt surgery. During the investigation, ICP was measured at baseline, and then a CSF sample was removed, resulting in pressure reduction. After this, ICP was regulated with an automated infusion protocol, with a maximum increase of 24 mm Hg above baseline. The pulsatility curve was thus determined in a wide range of ICP values. Gait improvement was defined as a gait speed increase ≥0.1 m/s.

Results

The pulsatility curve was unaltered by shunting. Baseline ICP and amplitude were reduced (−3.0±2.9 mm Hg; −1.1±1.5 mm Hg; p<0.05, n=51). Amplitude reduction was larger for gait improvers (−1.2±1.6 mm Hg, n=42) than non-improvers (−0.2±0.5 mm Hg, n=9) (p<0.05) although mean ICP reduction did not differ.

Conclusions

The pulsatility curve was not modified by shunt surgery, while the baseline position was shifted along the curve. Observed differences between gait improvers and non-improvers support cardiac related ICP pulsations as a component of INPH pathophysiology.
Effects of varying attentional focus on health-related physical fitness performance
Authors: Bredin Shannon S.D. , Dickson Danika B. , Warburton Darren E.R.
Published: February 2013

Assessing health-related physical fitness is important for determining health status. However, verbal instructions provided during an assessment generally do not specify direction of attentional focus. This investigation examined the effect of attentional focus on performance outcomes during appraisals of health-related physical fitness. Eight females (25.0 ± 4.0 years) and 8 males (26.3 ± 3.9 years) completed 7 physical fitness tests of the Canadian Physical Activity, Fitness and Lifestyle Approach (modified Canadian Aerobic Fitness Test, grip strength, push-ups, sit and reach, partial curl-ups, vertical jump, and back extension) on 3 different days, each separated by 1 week. On day 1, no attentional focus was specified. On days 2 and 3, participants were asked to adopt an external focus (instructions focused attention away from the body) or an internal focus (instructions focused attention on the body's movement) in randomized order. Irrespective of sex, adopting an external focus resulted in significantly better performance on all tests when compared with no focus or internal-focus conditions. An internal focus also resulted in performance decrements for grip strength, push-ups, and vertical jump vs. no focus. These results demonstrate that instructing individuals to adopt an external focus provides a performance advantage on appraisals of aerobic and musculoskeletal fitness, whereas an internal focus may hinder performance. In some participants, these scores may convert to a rating of health status that is 1 health benefit zone higher or lower, respectively. This highlights further the importance of formulating verbal instructions that incorporate attentional focus for optimal performance on appraisals of physical fitness.
Enhanced 5-fluorouracil cytotoxicity in high COX-2 expressing hepatocellular carcinoma cells by wogonin via the PI3K/Akt pathway
Authors: Zhao Li , Sha Yun-Ying , Zhao Qing , Yao Jing , Zhu Bin-Bin , Lu Zhi-Jian , You Qi-Dong , Guo Qing-Long
Published: February 2013

Combination therapies may increase the antitumor effects and reduce the adverse effects for the treatment of hepatocellular carcinoma. In this study, we determined the effects of 5-fluorouracil alone or in combination with wogonin in vitro and in vivo, and we investigated the possible mechanisms. The combination of these 2 drugs led to a decrease in survival and a significant synergistic inhibitory effect on high COX-2 expression in SMMC-7721 hepatocellular carcinoma (HCC) cells. Furthermore, the results show that this combination inhibits COX-2 expression and increases sensitivity to chemotherapeutic agents partly through regulating the PI3K/Akt signaling pathway. Moreover, the combination treatment caused a significant growth inhibition of human tumor xenografts in vivo. In conclusion, wogonin may increase the cytotoxicity of some antineoplastic agents and it can be used in combination with these agents as a novel therapeutic regimen for HCC treatment.
Nonlinear viscoelastic approach to model damage-associated performance behavior of asphaltic mixture and pavement structure
Authors: Ban Hoki , Im Soohyok , Kim Yong-Rak
Published: February 2013

This paper presents an integrated experimental–numerical effort to more accurately model the damage characteristics of asphalt mixtures and pavement structures than conventional elastic and (or) linear viscoelastic approaches can. To this end, Schapery's nonlinear viscoelastic constitutive model was implemented into a finite element software via user defined subroutine (user material, or UMAT) to analyze an asphalt pavement subjected to heavy truck loads. Then, a series of creep and recovery tests were conducted at various stress levels and at different temperatures to obtain the stress-dependent and temperature-sensitive viscoelastic material properties of asphalt mixtures. With the viscoelastic material properties characterized and the UMAT code, a typical pavement structure subjected to repeated heavy truck loads was modeled with the consideration of the effect of material nonlinearity with a realistic tire loading configuration. Three-dimensional finite element simulations of the pavement structure present significant differences between the linear viscoelastic approach and the nonlinear viscoelastic modeling in the prediction of pavement performance with respect to rutting and fatigue cracking. The differences between the two approaches underline the importance of proper and more realistic characterization of pavement materials and should be addressed in the process of performance-based pavement design.
Ants from the Miocene Totolapa amber (Chiapas, Mexico), with the first record of the genusForelius(Hymenoptera, Formicidae)
Authors: Durán-Ruiz Claudia , Riquelme Francisco , Coutiño-José Marco , Carbot-Chanona Gerardo , Castaño-Meneses Gabriela , Ramos-Arias Mario
Published: February 2013

Totolapa is one of the amber Lagerstätten from Chiapas, southwestern Mexico, which include the Simojovel and Huitiupán deposits. Despite the remarkable paleobiological heritage of Chiapas amber biota, the fossil record of ants from Totolapa has so far not been well studied. Based on exceptionally preserved specimens, four ant genera from the Totolapa amber deposits are reported in this paper, including Forelius, Azteca, Tapinoma, and Camponotus (Hymenoptera, Formicidae). Whereas the genera Azteca, Tapinoma, and Camponotus are previously known from amber quarries of Simojovel, this paper represents the first record of the presence of Forelius in Chiapas amber.
Nonlinear responses of white spruce growth to climate variability in interior Alaska
Authors: Lloyd Andrea H. , Duffy Paul A. , Mann Daniel H.
Published: February 2013

Ongoing warming at high latitudes is expected to lead to large changes in the structure and function of boreal forests. Our objective in this research is to determine the climatic controls over the growth of white spruce (Picea glauca (Moench) Voss) at the warmest driest margins of its range in interior Alaska. We then use those relationships to determine the climate variables most likely to limit future growth. We collected tree cores from white spruce trees growing on steep, south-facing river bluffs at five sites in interior Alaska, and analyzed the relationship between ring widths and climate using boosted regression trees. Precipitation and temperature of the previous growing season are important controls over growth at most sites: trees grow best in the coolest, wettest years. We identify clear thresholds in growth response to a number of variables, including both temperature and precipitation variables. General circulation model (GCM) projections of future climate in this region suggest that optimum climatic conditions for white spruce growth will become increasingly rare in the future. This is likely to cause short-term declines in productivity and, over the longer term, probably lead to a contraction of white spruce to the cooler, moister parts of its range in Alaska.
A new perspective on path integral quantum mechanics in curved space–time
Authors: Singh Dinesh , Mobed Nader
Published: February 2013

We present a new approach to path integral quantum mechanics in curved space–time for a scalar particle, expressed in terms of local curvature described by Fermi or Riemann normal coordinates. This approach correctly recovers the curved space–time free-particle Lagrangian, along with new terms that reveal a simultaneous breakdown of time-reversal symmetry and the weak equivalence principle at the particle's Compton wavelength scale. The formalism reveals a further prediction of a gravitational analogue of the Aharonov–Bohm effect and Berry's phase.
Southampton, Canada’s third pallasite
Authors: Kissin Stephen A. , MacRae Neil D. , Keays Reid R.
Published: February 2013

A. 3.58 kg pallasite meteorite was found in April 2001, near the mouth of the Saugeen River on Lake Huron (44°30.385′N, 81°22.330′W) by Carl Young of London, Ontario. The specimen is in the form of an irregular triaxial ellipsoid approximately 6.8 cm × 13.4 cm × 18.1 cm. Olivine crystals are visible on the smooth exterior surface which has a thin rind of oxidized iron. The sectioned interior contains olivine crystals with a considerable range in sizes up to approximately 2.5 cm diameter. Larger crystals have angular outlines and some are fractured, although corners and small grains are rounded. Apart from the kamacite and taenite of the metal phase, only small amounts of schreibersite and troilite are present. Analysis of the metal phase by instrumental neutron activation analysis (INAA) yielded Ni 97.4 mg/g, Ga 17.2 μg/g, Ge 77.8 μg/g, Ir 0.137 μg/g, and Au 2.12 μg/g. These values lie within the defined ranges for main group pallasites, except that Ge is ca. 20% higher. Analysis by inductively coupled plasma – mass spectrometry (ICP–MS) yielded Ir 0.0755 μg/g and Au 0.937 μg/g, differences attributed to difference in the mass and heterogeneity of the material analyzed. Olivines were found to have a mean composition of fayalite (Fa) 12.30, within the range of compositions for main group pallasites. Although the Hopewell Mounds of south-central Ohio contain fragments of the Brenham (Kansas) pallasite that were transported there by pre-contact people and are in the same region as the Southampton meteorite find, the apparent glacial transport of the newly found pallasite together with its compositional and textural differences indicate that it is a unique meteorite and the third pallasite found in Canada. The pallasite is named after the community of Southampton in which it was found.
A multispectral geological study of the Schrödinger impact basin
Authors: Shankar B. , Osinski G.R. , Antonenko I. , Neish C.D.
Published: February 2013

Schrödinger basin is a well-preserved peak-ring basin located on the lunar farside, along the rim of the much larger South Pole – Aitken (SPA) basin. The relatively young age (Lower Imbrian series, or 3.8 Ga) of this basin makes it an ideal site to study the geology of peak-ring basins in general, and the geological history of SPA specifically. Impact materials still recognizable include a well-defined crater rim, wall terraces, quasi-circular peak ring, and interior and exterior melt units. A small pyroclastic deposit fills a portion of the basin floor, along with several mare patches. This study uses Clementine multispectral ultraviolet–visible (UV–VIS) data, and a limited set of higher spectral resolution Chandrayaan-1 Moon Mineralogy Mapper (M3) data, as well as radar, camera, and topography data from the Lunar Reconnaissance Orbiter to better understand Schrödinger’s geology. Sampled spectral profiles and linear unmixing models applied to the Clementine data indicate there is a heterogeneous distribution of both anorthositic and basaltic materials in the crater floor. M3 data further validates this observation, and the high spectral resolution shows that most of the mafic content is dominated by pyroxene. These results challenge the traditional assumption that Schrödinger was formed in mostly highland terrain. Our assessment brings forth a new understanding regarding the placement of Schrödinger within SPA and the role SPA impact materials played in shaping the composition of Schrödinger.
Postcranial skeleton of
Postosuchus kirkpatricki
(Archosauria: Paracrocodylomorpha), from the Upper Triassic of the United States
Authors: Weinbaum Jonathan C.
Published: February 2013

Postosuchus kirkpatricki
is a Late Triassic (Norian) ‘rauisuchid’ archosaur from North America. The initial description of the
Postosuchus
type material included elements from two poposaurids. This confusion has prevented adequate description of the material. Recent examination of the type material and other specimens of
Postosuchus
, and of related taxa, has helped clarify the osteology of
Postosuchus
. The type specimens represent
c.
75% of the skeleton. Together with other referred material,
Postosuchus
remains one of the most completely known rauisuchids. The paratype skeleton, which is relatively complete, would have been
c.
3.5–4 m in length, and the holotype would have been closer to 5–6 m.

Analysis of the postcranial skeleton of
Postosuchus
suggests that it may have been an obligate biped (based in part on limb proportions, which are similar to some theropod dinosaurs, the size of the manus (30% of the size of the pes) and the highly reduced nature of the digits and vertebral measurements). Possible postcranial autapomorphies of
Postosuchus
include a large, rugose triangular supra-acetabular buttress confluent with the dorsal margin of the iliac blade, and a symmetrical pes with digits two and three being roughly equal in length.
Non-dinosaurian Dinosauromorpha
Authors: Langer Max C. , Nesbitt Sterling J. , Bittencourt Jonathas S. , Irmis Randall B.
Published: February 2013

Ichnological evidence suggests that dinosauromorphs originated by the Early Triassic, and skeletal remains of non-dinosaur representatives of the clade occur from the Anisian to the end of the Triassic. These taxa are small- to medium-sized, vary in feeding and locomotor features, and occurred over most of western Pangaea. They include the small lagerpetids from the Mid–Late Triassic of Argentina and the United States, and the larger, quadrupedal Silesauridae, with records in the Middle Triassic of Africa and Argentina, and in the Late Triassic of Europe, the Americas and northern Africa. The former group represents the earliest diverging dinosauromorphs, whereas silesaurids are more closely related to Dinosauria. Other dinosauromorphs include the archetypal early dinosauriform
Marasuchus lilloensis
(Middle Triassic of Argentina) and poorly known/controversial taxa such as
Lewisuchus admixtus
and
Saltopus elginensis
. The earliest diverging dinosauromorphs may have preyed on small animals (including insects), but cranio-dental remains are rare; by contrast, most silesaurids probably included plant material in their diet, as indicated by their modified jaw apparatus and teeth. Our knowledge of the anatomy and thus relationships of non-dinosaurian Dinosauromorpha is still deficient, and we suspect that future discoveries will continue to reveal novel patterns and hypotheses of palaeobiology and biogeography.
IFN-γ induces lipogenesis in mouse mesangial cells via the JAK2/STAT1 pathway
Authors: Hao Jun , Zhang Yu-jun , Lv Xin , Xu Ning , Liu Qin-juan , Zhao Song , Feng Xiao-juan , Xing Ling-ling , Kang Peng-peng , Li Gui-ying , Liu Shu-xia
Published: February 2013

The objective is to investigate the effect of high mobility group box-1 (HMGB1) on lipid deposition in γ-interferon (IFN-γ)-stimulated mouse mesangial cell line (MMC) and to determine whether the Janus kinase 2 and signal transducer and activator of transcription 1 (JAK2/STAT1) signaling pathway plays an important role in this process. We employed a control group, an IFN-γ stimulation group, and an IFN-γ + AG490 (JAK2 inhibitor) group. RNA interference aimed at sterol regulatory element-binding protein-1 (SREBP-1) or HMGB1 was used to investigate the effect of these proteins on IFN-γ-induced lipid deposition. Western blotting was used to detect phospho (p)-JAK2, JAK2, p-STAT1, STAT1, SREBP-1, fatty acid synthase (FAS), and HMGB1 protein expression. RT-PCR was used to detect SREBP-1, FAS, and HMGB1 mRNA. Oil Red O staining and the triglyceride assay were used to detect lipid deposition and triglyceride content. Results were as follows: 1) IFN-γ increased MMC cell lipid deposition, triglyceride content, and p-JAK2, p-STAT1, SREBP-1, and FAS expression; 2) SREBP-1 inhibition prevented FAS upregulation and attenuated IFN-γ-induced MMC cell lipid deposition and triglyceride content; 3) HMGB1 upregulated SREBP-1 and FAS mRNA and protein levels, which increased lipid deposition in MMC cells. Small interfering RNA-mediated inhibition of HMGB1 decreased SREBP-1 and FAS expression and lipid accumulation; 4) AG490 decreased upregulation of HMGB1 and p-JAK2/p-STAT1, as well as IFN-γ-induced lipogenesis. In conclusion, the JAK2/STAT1 pathway mediates IFN-γ-induced lipogenesis in MMC cells through regulation of HMGB1/SREBP-1/FAS.
Skeletal muscle PLIN proteins, ATGL and CGI-58, interactions at rest and following stimulated contraction
Authors: MacPherson Rebecca E. K. , Ramos Sofhia V. , Vandenboom Rene , Roy Brian D. , Peters Sandra J.
Published: February 2013

Evidence indicates that skeletal muscle lipid droplet-associated proteins (PLINs) regulate lipolysis through protein-protein interactions on the lipid droplet surface. In adipocytes, PLIN1 is thought to regulate lipolysis by directly interacting with comparative gene identification-58 (CGI-58), an activator of adipose triglyceride lipase (ATGL). Upon lipolytic stimulation, PLIN1 is phosphorylated, releasing CGI-58 to fully activate ATGL and initiate triglyceride breakdown. The absence of PLIN1 in skeletal muscle leads us to believe that other PLIN family members undertake this role. Our purpose was to examine interactions between PLIN2, PLIN3, and PLIN5, with ATGL and its coactivator CGI-58 at rest and following contraction. Isolated rat solei were incubated for 30 min at rest or during 30 min of intermittent tetanic stimulation [150-ms volleys at 60 Hz with a train rate of 20 tetani/min (25°C)] to maximally stimulate intramuscular lipid breakdown. Results show that the interaction between ATGL and CGI-58 increased 128% following contraction ( P = 0.041). Further, ATGL interacts with PLIN2, PLIN3, and PLIN5 at rest and following contraction. The PLIN2-ATGL interaction decreased significantly by 21% following stimulation ( P = 0.013). Both PLIN3 and PLIN5 coprecipitated with CGI-58 at rest and following contraction, while there was no detectable interaction between PLIN2 and CGI-58 in either condition. Therefore, our findings indicate that in skeletal muscle, during contraction-induced muscle lipolysis, ATGL and CGI-58 strongly associate and that the PLIN proteins work together to regulate lipolysis, in part, by preventing ATGL and CGI-58 interactions at rest.
Sensory nerves and nitric oxide contribute to reflex cutaneous vasodilation in humans
Authors: Wong Brett J.
Published: February 2013

We tested the hypothesis that inhibition of cutaneous sensory nerves would attenuate reflex cutaneous vasodilation in response to an increase in core temperature. Nine subjects were equipped with four microdialysis fibers on the forearm. Two sites were treated with topical anesthetic EMLA cream for 120 min. Sensory nerve inhibition was verified by lack of sensation to a pinprick. Microdialysis fibers were randomly assigned as 1) lactated Ringer (control); 2) 10 mM nitro-l-arginine methyl ester (l-NAME) to inhibit nitric oxide synthase; 3) EMLA + lactated Ringer; and 4) EMLA + l-NAME. Laser-Doppler flowmetry was used as an index of skin blood flow, and blood pressure was measured via brachial auscultation. Subjects wore a water-perfused suit, and oral temperature was monitored as an index of core temperature. The suit was perfused with 50°C water to initiate whole body heat stress to raise oral temperature 0.8°C above baseline. Cutaneous vascular conductance (CVC) was calculated and normalized to maximal vasodilation (%CVCmax). There was no difference in CVC between control and EMLA sites (67 ± 5 vs. 69 ± 6% CVCmax), but the onset of vasodilation was delayed at EMLA compared with control sites. The l-NAME site was significantly attenuated compared with control and EMLA sites (45 ± 5% CVCmax; P < 0.01). Combined EMLA + l-NAME site (25 ± 6% CVCmax) was attenuated compared with control and EMLA ( P < 0.001) and l-NAME only ( P < 0.01). These data suggest cutaneous sensory nerves contribute to reflex cutaneous vasodilation during the early, but not latter, stages of heat stress, and full expression of reflex cutaneous vasodilation requires functional sensory nerves and NOS.
Acute endurance exercise induces changes in vasorelaxation responses that are vessel-specific
Authors: Murias Juan M. , Grise Kenneth N. , Jiang Mao , Kowalchuk Hana , Melling C. W. James , Noble Earl G.
Published: February 2013

The dynamic adjustment and amplitude of the endothelium-dependent vasorelaxation of the carotid, aorta, iliac, and femoral vessels were measured in response to acute low- (LI) or high-intensity (HI) endurance exercise. Vasorelaxation to 10−4 M ACh was evaluated in 10 control, 10 LI, and 10 HI rats. Two-millimeter sections of carotid, aorta, iliac, and femoral arteries were mounted onto a myography system. Vasorelaxation responses were modeled as a monoexponential function. The overall τ (control, 10.5 ± 6.0 s; LI, 10.4 ± 5.7 s; HI, 11.0 ± 6.9 s) and time-to-steady-state (control, 47.6 ± 24.0 s; LI, 46.2 ± 22.8 s; HI, 49.1 ± 28.3 s) was similar in LI, HI, and control ( P > 0.05). The overall (average of four vessel-type) % vasorelaxation was larger in LI (73 ± 16%) and HI (73 ± 16%) than in control (66 ± 19%) ( P < 0.05). The overall rate of vasorelaxation was greater in LI (1.9 ± 0.9%·s−1) and HI (1.9 ± 1.1%·s−1) compared with control (1.6 ± 0.7%·s−1) ( P < 0.05). The vessel-specific responses (average response for the three conditions) showed that carotid displayed a slower adjustment (τ, 18.9 ± 4.4 s; time-to-steady-state, 80.4 ± 18.4 s) compared with the aorta (τ, 10.3 ± 3.8 s; time-to-steady-state, 46.3 ± 15.2 s), the iliac (τ, 6.3 ± 2.1 s; time-to-steady-state, 30.3 ± 9.0 s), and the femoral (τ, 6.0 ± 1.9 s; time-to-steady-state, 29.3 ± 8.4 s). The % vasorelaxation was larger in the carotid (82 ± 14%) than in the aorta (67 ± 16%), iliac (61 ± 13%), and femoral (71 ± 19%) ( P > 0.05). The rate of vasorelaxation was carotid (1.1 ± 0.2%·s−1), aorta (1.5 ± 0.4%·s−1), iliac (2.2 ± 0.8%·s−1), and femoral (2.6 ± 1.0%·s−1). In conclusion, an acute bout of endurance exercise increased vascular responsiveness. The dynamic and percent adjustments were vessel-specific with vessel function likely determining the response.
Antenatal betamethasone has a sex-dependent effect on the in vivo response to endothelin in adult sheep
Authors: Lee Jeong-Heon , Zhang Jie , Flores Lourdes , Rose James C. , Massmann G. Angela , Figueroa Jorge P.
Published: February 2013

Antenatal steroid administration is associated with multiple cardiometabolic alterations, including hypertension; however, the mechanisms underlying this phenomenon are unclear. The aim of the present study was to ascertain, in vivo, the contribution of the endothelin system to the development of hypertension in the adult offspring and the signaling pathway involved. Pregnant sheep were treated with two doses of betamethasone ( n = 23) or vehicle ( n = 22) at 80 days (∼0.55) gestation and allowed to deliver at term. Adult sheep were chronically instrumented under general anesthesia to place vascular catheters and a femoral artery flow probe. Blood pressure and flow were recorded continuously, and femoral artery vascular resistance was calculated before and during administration of endothelin 1 (ET-1). Selective blockers (dantrolene, BQ123, niacinamide) or saline were administered simultaneously. Betamethasone-exposed animals exhibited a significant elevation in mean blood pressure (female: 98 ± 1.8 vs. 92 ± 2.1; males: 97 ± 3.4 vs. 90 ± 2.3; mmHg; P < 0.05). ET-1 elicited a significant increase in blood pressure ( F = 56.4; P < 0.001) and in vascular resistance ( F = 44.3; P < 0.001) in all groups. A betamethasone effect in the vascular resistance response to ET-1 ( F = 25.7; P < 0.001) was present in females only, and the effect was partially blunted by niacinamide ( F = 6.6; P < 0.01). Combined administration of niacinamide and BQ123, as well as of dantrolene abolished the betamethasone effect on vascular resistance. No significant differences in mRNA expression of ETAor ETBin endothelial or smooth muscle cells of resistance-size arteries were observed. We conclude that the betamethasone effect on vascular resistance is mediated by an enhanced response to ET-1 through ETAreceptor via the cyclic ADPR/ryanodine pathway.
Renal sensory and sympathetic nerves reinnervate the kidney in a similar time-dependent fashion after renal denervation in rats
Authors: Mulder Jan , Hökfelt Tomas , Knuepfer Mark M. , Kopp Ulla C.
Published: February 2013

Efferent renal sympathetic nerves reinnervate the kidney after renal denervation in animals and humans. Therefore, the long-term reduction in arterial pressure following renal denervation in drug-resistant hypertensive patients has been attributed to lack of afferent renal sensory reinnervation. However, afferent sensory reinnervation of any organ, including the kidney, is an understudied question. Therefore, we analyzed the time course of sympathetic and sensory reinnervation at multiple time points (1, 4, and 5 days and 1, 2, 3, 4, 6, 9, and 12 wk) after renal denervation in normal Sprague-Dawley rats. Sympathetic and sensory innervation in the innervated and contralateral denervated kidney was determined as optical density (ImageJ) of the sympathetic and sensory nerves identified by immunohistochemistry using antibodies against markers for sympathetic nerves [neuropeptide Y (NPY) and tyrosine hydroxylase (TH)] and sensory nerves [substance P and calcitonin gene-related peptide (CGRP)]. In denervated kidneys, the optical density of NPY-immunoreactive (ir) fibers in the renal cortex and substance P-ir fibers in the pelvic wall was 6, 39, and 100% and 8, 47, and 100%, respectively, of that in the contralateral innervated kidney at 4 days, 4 wk, and 12 wk after denervation. Linear regression analysis of the optical density of the ratio of the denervated/innervated kidney versus time yielded similar intercept and slope values for NPY-ir, TH-ir, substance P-ir, and CGRP-ir fibers (all R2> 0.76). In conclusion, in normotensive rats, reinnervation of the renal sensory nerves occurs over the same time course as reinnervation of the renal sympathetic nerves, both being complete at 9 to 12 wk following renal denervation.
Netrin-1-treated macrophages protect the kidney against ischemia-reperfusion injury and suppress inflammation by inducing M2 polarization
Authors: Ranganathan Punithavathi Vilapakkam , Jayakumar Calpurnia , Ramesh Ganesan
Published: February 2013

Improper macrophage activation is pathogenically linked to various metabolic, inflammatory, and immune disorders. Therefore, regulatory proteins controlling macrophage activation have emerged as important new therapeutic targets. We recently demonstrated that netrin-1 regulates inflammation and infiltration of monocytes and ameliorates ischemia-reperfusion-induced kidney injury. However, it was not known whether netrin-1 regulates the phenotype of macrophages and the signaling mechanism through which it might do this. In this study, we report novel mechanisms underlying netrin-1's effects on macrophages using in vivo and in vitro studies. Overexpression of netrin-1 in spleen and kidney of transgenic mice increased expression of arginase-1, IL-4, and IL-13 and decreased expression of COX-2, indicating a phenotypic switch in macrophage polarization toward an M2-like phenotype. Moreover, flow cytometry analysis showed a significant increase in mannose receptor-positive macrophages in spleen compared with wild type. In vitro, netrin-1 induced the expression of M2 marker expression in bone marrow-derived macrophages, peritoneal macrophages, and RAW264.7 cells, and suppressed IFNγ-induced M1 polarization and production of inflammatory mediators. Adoptive transfer of netrin-1-treated macrophages suppressed inflammation and kidney injury against ischemia-reperfusion. Netrin-1 activated PPAR pathways and inhibition of PPAR activation abolished netrin-1-induced M2 polarization and suppression of cytokine production. Consistent with in vitro studies, administration of PPAR antagonist to mice abolished the netrin-1 protective effects against ischemia-reperfusion injury of the kidney. These findings illustrate that netrin-1 regulates macrophage polarization through PPAR pathways and confers anti-inflammatory actions in inflammed kidney tissue.
Nitric oxide in afferent arterioles after uninephrectomy depends on extracellularl-arginine
Authors: Helle Frank , Skogstrand Trude , Schwartz Idit F. , Schwartz Doron , Iversen Bjarne M. , Palm Fredrik , Hultström Michael
Published: February 2013

Uninephrectomy (UNX) causes hyperperfusion of the contralateral remaining kidney via increased nitric oxide (NO) synthesis. Although the exact mechanism remains largely unknown, we hypothesize that this would be localized to the afferent arteriole and that it depends on cellular uptake of l-arginine. The experiments were performed in rats 2 days (early) or 6 wk (late) after UNX and compared with controls (Sham) to study acute and chronic effects on NO metabolism. Renal blood flow was increased after UNX (21 ± 2 ml·min−1·kg−1in sham, 30 ± 3 in early, and 26 ± 1 in late, P < 0.05). NO inhibition with Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME) caused a greater increase in renal vascular resistance in early UNX compared with Sham and late UNX (138 ± 24 vs. 88 ± 10, and 84 ± 7%, P < 0.01). The lower limit of autoregulation was increased both in early and late UNX compared with Sham ( P < 0.05). l-NAME did not affect the ANG II-induced contraction of isolated afferent arterioles (AA) from Sham. AA from early UNX displayed a more pronounced contraction in response to l-NAME (−57 ± 7 vs. −16 ± 7%, P < 0.05) and in the absence of l-arginine (−41 ± 4%, P < 0.05) compared with both late UNX and Sham. mRNA expression of endothelial NO synthase was reduced, whereas protein expression was unchanged. Cationic amino acid transporter-1 and -2 mRNA was increased, while protein was unaffected in isolated preglomerular resistance vessels. In conclusion, NO-dependent hyperperfusion of the remaining kidney in early UNX is associated with increased NO release from the afferent arteriole, which is highly dependent on extracellular l-arginine availability.