bluuebunny/crossref_metadata_2025 huggingface dataset:
Early propranolol treatment induces lung heme-oxygenase-1, attenuates metabolic dysfunction, and improves survival following experimental sepsis
Authors: Wilson Joel , Higgins David , Hutting Haley , Serkova Natalie , Baird Christine , Khailova Ludmila , Queensland Kelly , Vu Tran Zung , Weitzel Lindsay , Wischmeyer Paul E
Published: September 2013

Introduction

Pharmacological agents that block beta-adrenergic receptors have been associated with improved outcome in burn injury. It has been hypothesized that injuries leading to a hypermetabolic state, such as septic shock, may also benefit from beta-blockade; however, outcome data in experimental models have been contradictory. Thus, we investigated the effect of beta-blockade with propranolol on survival, hemodynamics, lung heat shock protein (HSP) expression, metabolism and inflammatory markers in a rat cecal ligation and puncture (CLP) model of sepsis.

Methods

Sprague-Dawley rats receiving either repeated doses (30 minutes pre-CLP and every 8 hours for 24 hours postoperatively) of propranolol or control (normal saline), underwent CLP and were monitored for survival. Additionally, lung and blood samples were collected at 6 and 24 hours for analysis. Animals also underwent monitoring to evaluate global hemodynamics.

Results

Seven days following CLP, propranolol improved survival versus control (P < 0.01). Heart rates in the propranolol-treated rats were approximately 23% lower than control rats (P < 0.05) over the first 24 hours, but the mean arterial blood pressure was not different between groups. Metabolic analysis of lung tissue demonstrated an increase in lung ATP/ADP ratio and NAD+ content and a decreased ratio of polyunsaturated fatty acids to monounsaturated fatty acids (PUFA/MUFA). Cytokine analysis of the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) demonstrated decreased expression of TNF-alpha in both lung and plasma at 24 hours post CLP induced sepsis. Finally, propranolol led to a significant increase in lung hemeoxygenase-1 expression, a key cellular protective heat shock protein (HSP) in the lung. Other lung HSP expression was unchanged.

Conclusions

These results suggest that propranolol treatment may decrease mortality during sepsis potentially via a combination of improving metabolism, suppressing aspects of the inflammatory response and enhancing tissue protection.
β-Catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8+ T cells
Authors: Liang Xinjun , Fu Chunmei , Cui Weiguo , Ober-Blöbaum Julia L , Zahner Sonja P , Shrikant Protul A , Clausen Björn E , Flavell Richard A , Mellman Ira , Jiang Aimin
Published: September 2013

Whereas CD8+ T cells are essential for anti-tumor immunity, tumors often evade CD8+ T cell surveillance by immunosuppression. As the initiators of antigen-specific immune responses, DCs are likely to play a central role in regulating the balance between immunity and tolerance to tumor antigens and are specialized in their ability to cross-present exogenous tumor antigens on MHC class I molecules to initiate CD8+ T cell immunity. However, it remains unclear whether and how tumors modulate DC functions to suppress CD8+ T cell responses. We have shown previously that β-catenin signaling in DCs promotes DC-mediated CD4+ T cell tolerance. Here, we tested the hypothesis that β-catenin in DCs mediates tumor-induced suppression of CD8+ T cell immunity by inhibiting the ability of DCs in cross-priming. β-Catenin was activated in DCs by multiple tumors in vivo and in vitro. B16 melanoma-bearing mice, when vaccinated with DC-targeting anti-DEC-205 mAb fused with tumor antigens, exhibited dampened CD8+ immunity, similar to DC-β-cateninactive mice. DCs from DC-β-cateninactive and tumor-bearing mice were deficient in cross-priming, and antigen-specific CD8+ T cells primed in these mice resulted in dampened CD8+ memory responses. Importantly, DC-β-catenin−/− mice completely abrogate tumor-mediated inhibition of cross-priming, suggesting that tumor-induced inhibition of cross-priming is dependent on β-catenin. Finally, enhancing cross-priming at the priming or recall phase rescued β-catenin-suppressed CD8+ immunity in DC-β-cateninactive and tumor-bearing mice. Thus, β-catenin-mediated inhibition of cross-priming represents a new and potentially general mechanism that tumors employ to achieve immunosuppression.
Integrated geophysical imaging of a concealed mineral deposit: A case study of the world-class Pebble porphyry deposit in southwestern Alaska
Authors: Shah Anjana K. , Bedrosian Paul A. , Anderson Eric D. , Kelley Karen D. , Lang James
Published: September 2013

We combined aeromagnetic, induced polarization, magnetotelluric, and gravity surveys as well as drillhole geologic, alteration, magnetic susceptibility, and density data for exploration and characterization of the Cu-Au-Mo Pebble porphyry deposit. This undeveloped deposit is almost completely concealed by postmineralization sedimentary and volcanic rocks, presenting an exploration challenge. Individual geophysical methods primarily assist regional characterization. Positive chargeability and conductivity anomalies are observed over a broad region surrounding the deposit, likely representing sulfide minerals that accumulated during multiple stages of hydrothermal alteration. The mineralized area occupies only a small part of the chargeability anomaly because sulfide precipitation was not unique to the deposit, and mafic rocks also exhibit strong chargeability. Conductivity anomalies similarly reflect widespread sulfides as well as water-saturated glacial sediments. Mineralogical and magnetic susceptibility data indicate magnetite destruction primarily within the Cu-Au-Mo mineralized area. The magnetic field does not show a corresponding anomaly low but the analytic signal does in areas where the deposit is not covered by postmineralization igneous rocks. The analytic signal shows similar lows over sedimentary rocks outside of the mineralized area, however, and cannot uniquely distinguish the deposit. We find that the intersection of positive chargeability anomalies with analytic signal lows, indicating elevated sulfide concentrations but low magnetite at shallow depths, roughly delineates the deposit where it is covered only by glacial sediments. Neither chargeability highs nor analytic signal lows are present where the deposit is covered by several hundred meters of sedimentary and volcanic rocks, but a 3D resistivity model derived from magnetotelluric data shows a corresponding zone of higher conductivity. Gravity data highlight geologic features within the deposit, including shallow diorite sills that locally contain higher-grade mineralization. The results thus show ways in which an integrated survey approach might be used to distinguish zones of potentially economic mineralization.
Chemical Stability of Secondary-alkanolamine-based CO2 Solvents under Stripping Conditions
Authors: Yamamoto Shin , Higashii Takayuki
Published: September 2013

Chemical stabilities of secondary alkanolamine substrates in CO2 solvents under stripping conditions and generation pathways of thermal degradation products have been studied. The two products generated in each amine solution have been proven to be oxazolidone and dimer of each amine. The thermal degradation of secondary alkanolamine proceeds in two steps as consecutive reactions. The carbamate compound, which is CO2-absorbing amine, cyclodehydrates to generate oxazolidone, and the oxazolidone further reacts with another amine to generate dimer through decarbonation condensation.
Short- and long-term habituation of auditory event-related potentials in the rat
Authors: Gurevicius Kestutis , Lipponen Arto , Minkeviciene Rimante , Tanila Heikki
Published: September 2013

An auditory oddball paradigm in humans generates a long-duration cortical negative potential, often referred to as mismatch negativity. Similar negativity has been documented in monkeys and cats, but it is controversial whether mismatch negativity also exists in awake rodents. To this end, we recorded cortical and hippocampal evoked responses in rats during alert immobility under a typical passive oddball paradigm that yields mismatch negativity in humans. The standard stimulus was a 9 kHz tone and the deviant either 7 or 11 kHz tone in the first condition. We found no evidence of a sustained potential shift when comparing evoked responses to standard and deviant stimuli. Instead, we found repetition-induced attenuation of the P60 component of the combined evoked response in the cortex, but not in the hippocampus. The attenuation extended over three days of recording and disappeared after 20 intervening days of rest. Reversal of the standard and deviant tones resulted is a robust enhancement of the N40 component not only in the cortex but also in the hippocampus. Responses to standard and deviant stimuli were affected similarly. Finally, we tested the effect of scopolamine in this paradigm. Scopolamine attenuated cortical N40 and P60 as well as hippocampal P60 components, but had no specific effect on the deviant response. We conclude that in an oddball paradigm the rat demonstrates repetition-induced attenuation of mid-latency responses, which resembles attenuation of the N1-component of human auditory evoked potential, but no mismatch negativity.
Oedema is associated with clinical outcome following emergency abdominal surgery
Authors: Vaughan-Shaw PG , Saunders J , Smith T , King AT , Stroud MA
Published: September 2013

Introduction

Oedema is observed frequently following surgery and may be associated with worse outcomes. To date, no study has investigated the role of oedema in the emergency surgical patient. This study assesses the incidence of oedema following emergency abdominal surgery and the value of early postoperative oedema measurement in predicting clinical outcome.

Methods

A prospective cohort study of patients undergoing emergency abdominal surgery at a university unit over a two-month period was undertaken. Nutritional and clinical outcome data were collected and oedema was measured in the early postoperative period. Predictors of oedema and outcomes associated with postoperative oedema were identified through univariate and multivariate analysis.

Results

Overall, 55 patients (median age: 66 years) were included in the study. Postoperative morbidity included ileus (n=22) and sepsis (n=6) with 12 deaths at follow-up. Postoperative oedema was present in 19 patients and was associated with prolonged perioperative fasting (107 vs 30 hours, p=0.009) but not with body mass index (24kg/m2 vs 27kg/m2, p=0.169) or preadmission weight loss (5% vs 3%, p=0.923). On multivariate analysis, oedema was independently associated with gastrointestinal recovery (B=6.91, p=0.038), artificial nutritional support requirement (odds ratio: 6.91, p=0.037) and overall survival (χ2=13.1, df=1, p=0.001).

Conclusions

Generalised oedema is common after emergency abdominal surgery and appears to independently predict gastrointestinal recovery, the need for artificial nutritional support and survival. Oedema is not associated with commonly applied markers of nutritional status such as body mass index or recent weight loss. Measurement of oedema offers utility in identifying those at risk of poor clinical outcome or those requiring artificial nutritional support following emergency abdominal surgery.
A critical inventory of preoperative skull replicas
Authors: Fasel JHD , Beinemann J , Schaller K , Gailloud P
Published: September 2013

Introduction

Physical replicas of organs are used increasingly for preoperative planning. The quality of these models is generally accepted by surgeons. In view of the strong trend towards minimally invasive and personalised surgery, however, the aim of this investigation was to assess qualitatively the accuracy of such replicas, using skull models as an example.

Methods

Skull imaging was acquired for three cadavers by computed tomography using clinical routine parameters. After digital three-dimensional (3D) reconstruction, physical replicas were produced by 3D printing. The facsimilia were analysed systematically and compared with the best gold standard possible: the macerated skull itself.

Results

The skull models were far from anatomically accurate. Non-conforming rendering was observed in particular for foramina, sutures, notches, fissures, grooves, channels, tuberosities, thin-walled structures, sharp peaks and crests, and teeth.

Conclusions

Surgeons should be aware that preoperative models may not yet render the exact anatomy of the patient under consideration and are advised to continue relying, in specific conditions, on their own analysis of the native computed tomography or magnetic resonance imaging.
Oxford elbow scores in an asymptomatic population
Authors: Guyver PM , Cattell AE , Hall MJ , Brinsden MD
Published: September 2013

Introduction

Patient reported outcome measures (PROMs) are being used increasingly to assess the quality of healthcare delivery in the UK. It is important when using PROMs to know the score of the background population against which any clinical intervention may be benchmarked. The purpose of this study was to measure an elbow specific PROM for the population of the South West Peninsula.

Methods

A cross-sectional survey was undertaken of patients and healthcare professionals from the South West Peninsula population. Participants were asked to complete a simple demographic questionnaire and an Oxford elbow score for each elbow. Respondents with a history of elbow surgery, elbow injury, chronic elbow problems or an incomplete dataset were excluded from the study.

Results

A total of 1,765 respondents (3,530 elbows) completed the survey but 567 questionnaires were excluded due to incomplete datasets, pre-existing elbow pathology or age criteria, leaving 1,198 individuals (2,396 elbows) for analysis. The median scores for each decade group were 48, with mean scores ranging from 46.74 to 47.94. There was no significant clinical difference in the scores for age, sex or hand dominance.

Conclusions

When using the Oxford elbow score to assess outcomes after surgery, a normal score should be used as the benchmark. This benchmark is independent of age, sex and hand dominance.
Spiral Jetty, thirty-seven years later: The cinematic time of James Benning
Authors: Butler Alison
Published: September 2013

This article considers cinematic time in James Benning’s film, casting a glance (2007), in relation to its subject, Robert Smithson’s 1970 earthwork Spiral Jetty, and his film of the same name. The radicalism of Smithson’s thinking on time has been widely acknowledged, and his influence continues to pervade contemporary artistic practice. The relationship of Benning’s films with this legacy may appear somewhat oblique, given their apparent phenomenological rendition of ‘real time’. However, closer examination of Benning’s formal strategies reveals a more complex temporal construction, characterized by uncertain intervals that interrupt the folding of cinematic time into the flow of consciousness. Smithson’s film uses cinematic analogy to gesture towards vast reaches of geological time; Benning’s film creates a simulated timescale to evoke the short history of the earthwork itself. Smithson’s embrace of the entropic was a counter-cultural stance at the end of the1960s, but under the shadow of ecological disaster, this orientation has come to appear melancholy and romantic rather than radical. Benning’s film returns the jetty to anthropic time, but raises questions about the ways we inhabit time. His practice of working with ‘borrowed time’ is particularly suited to the cultural and historical moment of his later work.
Warped product Einstein metrics on homogeneous spaces and homogeneous Ricci solitons
Authors: He Chenxu , Petersen Peter , Wylie William
Published: September 2013

In this paper we consider connections between Ricci solitons and Einstein metrics on homogeneous spaces. We show that a semi-algebraic Ricci soliton admits an Einstein one-dimensional extension if the soliton derivation can be chosen to be normal. Using our previous work on warped product Einstein metrics, we show that every normal semi-algebraic Ricci soliton also admits a k-dimensional Einstein extension for any k ≥ 2. We also prove converse theorems for these constructions and some geometric and topological structure results for homogeneous warped product Einstein metrics. In the appendix we give an alternative approach to semi-algebraic Ricci solitons which naturally leads to a definition of semi-algebraic Ricci solitons in the non-homogeneous setting.
Do Political Institutions and Culture Jointly Matter for Financial Development? A Cross-Country Panel Investigation
Authors: Mukherjee Deepraj , Dutta Nabamita
Published: September 2013

This article investigates the role of political institutions and culture in creating an efficient financial infrastructure for a country. It further delves into this relationship and addresses the question: do both types of institutions mentioned above affect financial development of a country, jointly? Our findings support the established notion in the literature that institutions matter for financial development. We show both these types of institutions – political institutions and culture – jointly promote financial development. Further, our result stresses that these two types of institutions behave as complements – the presence of efficient political institutions augment the effectiveness of culture and, thus, financial development is enhanced. Our results are robust to various proxies of institutions and alternate estimation models.
Shedding Light on the Recent U.S.–China Solar Dispute
Authors: Clark Don P.
Published: September 2013

This paper reviews the highly politicized recent decision by the U.S. to impose large dumping and countervailing duties on solar cells and modules imported from China. Attention is devoted to discussing the case, the conflict between the Obama administration’s trade policy and environmental goals, shortcomings inherent in the investigations related to solar imports, China’s response to the allegations, the impact on downstream firms that install solar panels, and the future of U.S.–China trade relations. U.S. trade policy is sending a negative signal to the rest of the world that will only encourage retaliation and obstruct the solar sector’s development. Punitive duties are inconsistent with President Obama’s energy and export initiatives. The U.S. should refrain from transforming trade policy mistakes into energy/environmental and export policy failures.
Predicting the Liquid Film Thickness and Droplet–Gas Flow in Effervescent Atomization: Influence of Operating Conditions and Fluid Viscosity
Authors: Liu Meng , Duan Yufeng
Published: September 2013

The droplet–gas flow in effervescent atomization was simulated using a comprehensive numerical model. Liquid film thicknesses in the nozzle exit orifice and droplet size distribution at the downstream of spray were calculated. The thickness of liquid film in the nozzle exit orifice increased and approached the droplet size in the primary atomization, as the air–liquid ratio increased. The primary breakup model can accurately predict the Sauter mean diameter in the primary atomization when gas–liquid two-phase flow belongs to the annular flow in the nozzle exit orifice. The viscosity of fluid had minimal influence on the liquid film thickness for spray with fluids, the viscosity of which is significantly greater than that of water. Droplet size initially decreased and then increased along the axial distance because of the secondary atomization and droplet coalescence at the downstream of spray.
Identification of the curve of discontinuity of the determinant of the anisotropic conductivity
Authors: Ikehata M.
Published: September 2013

- Consider an anisotropic conductor of electric current which occupies a domain Ω ⊂ℝ2 with conductivity coefficient A = A0 +BχD, where D is a subdomain of Ω, A0 and A0+B are real, symmetric, uniformly positive definite and 2×2-matrix-valued functions. Denote by ΛA(f) the flux across ∂Ω induced by an electric potential f on ∂Ω. We prove that D can be uniquely determined by ΛA(f) for infinitely many f provided det A is discontinuous on ∂D and B is small on ∂D.
Integral geometry problems for symmetric tensor fields with incomplete data
Authors: Vertgeim L. B.
Published: September 2013

- The paper is devoted to the reconstruction problems of a compactly supported symmetric tensor field in ℝn , if its ray transform is known along the lines, intersecting a given curve. Two versions of the reconstruction are considered.
The problem of dynamical reconstruction of Dirichlet boundary control in semilinear hyperbolic equations
Authors: Maksimov V. , Pandolfi L.
Published: September 2013

- The problems of dynamical reconstruction of unknown distributed and boundary controls acting upon nonlinear hyperbolic equations are discussed. Regularized algorithms which reconstruct unknown input during the evolution of the process are designed. These algorithms are stable with respect to informational noises and computational errors.
Reciprocity principle and crack identification in transient thermal problems
Authors: A. Ben Abda , Bui H.D.
Published: September 2013

- We consider the inverse problem of crack determination related to the nondestructive thermal testing of materials process. Using arbitrary transient heat flux applied to the external boundary and measuring the induced temperature, we prove that the overspecified datum suffice to reconstruct planar cracks.
The problem of determining a coefficient in the parabolic equation and some properties of its solution
Authors: Belov Yu. Ya. , Shipina T.N.
Published: September 2013

- An inverse problem of recovering a coefficient of the parabolic equation is considered in the case when the unknown coefficient depends only on the time variable t. The inverse problem is proved to be uniquely solvable “on the whole”. The behavior of its solution, when t →+∞, is investigated.
Unique continuation for over-determined Kirchoff plate equations and related thermoelastic systems
Authors: Eller M. , Lasiecka I. , Triggiani R.
Published: September 2013

- We present unique continuation results for two over-determined problems: one involving a Kirchoff plate equation and one involving a related thermoelastic system, both with variable coefficient transmission coefficient and zero Cauchy data on an arbitrarily small portion of the boundary. Besides being of interest in themselves, both these two unique continuation results are critically invoked in the solution of a controllability problem (exact in the mechanical variables {w,wt} and, simultaneously, approximate in the thermal variable θ) of thermoelastic plates, by means of boundary controls, either in the hinged/Dirichlet boundary conditions, or else in the clamped/Dirichlet boundary conditions [E-L-T.1]-[E-L-T.3].
Optimal control methods in inverse problems and computational processes
Authors: Agoshkov V. I.
Published: September 2013

- The paper presents results related to application of optimal control methods to investigation and solution of a class of inverse problems. Applications of these methods to particular inverse problems are considered.
Iterative methods for an inverse heat conduction problem
Authors: Bastay G. , Kozlov V.A. , Turesson B.O.
Published: September 2013

- We consider the problem of reconstruction of the temperature from measurements of the temperature and heat flux on a part of the boundary and present iterative methods for solving this problem. The characteristic feature of the methods is the fact that in each iteration step, well-posed problems for the same equation are solved. The regularizing character of the methods comes from suitable choice of boundary conditions. This fact allows one to use standard numerical packages. Some numerical experiments are given.
Identification of a special class of memory kernels in one-dimensional heat flow
Authors: Janno J. , Wolfersdorf L.V.
Published: September 2013

- We consider the inverse problem of identification of memory kernels in one-dimensional heat flow are dealt with where the kernel is represented by a finite sum of products of known spatially-dependent functions and unknown time-dependent functions. As additional conditions for the inverse problems observations of both heat flux and temperature are prescribed. Using the Laplace transform method we prove an existence and uniqueness theorem for the memory kernel.
Identification of a temperature dependent heat conductivity by Tikhonov regularization
Authors: Kügler P. , Engl H.W.
Published: September 2013

- If one applies the standard theory of Tikhonov regularization to the nonlinear ill-posed problem of identifying a temperature-dependent heat conductivity from temperature measurements, one needs rather strong conditions for obtaining convergence rates. By using a problem-adapted adjoint, we can obtain convergence rates under substantially weaker and more realistic conditions.
Convergence rates of the continuous regularized Gauss—Newton method
Authors: Kaltenbacher B. , Neubauer A. , Ramm A.G.
Published: September 2013

- In this paper a convergence proof is given for the continuous analog of the Gauss-Newton method for nonlinear ill-posed operator equations and convergence rates are obtained. Convergence for exact data is proved for nonmonotone operators under weaker source conditions than before. Moreover, nonlinear ill-posed problems with noisy data are considered and a priori and a posteriori stopping rules are proposed. These rules yield convergence of the regularized approximations to the exact solution as the noise level tends to zero. The convergence rates are optimal rates under the source conditions considered.
Generalized Arcangeli’s discrepancy principles for a class of regularization methods for solving ill-posed problems
Authors: Nair M. T. , Rajan M.P.
Published: September 2013

- While applying regularization procedures for obtaining stable solutions of ill-posed problems, one of the crucial step is the choice of the regularization parameter. Among the well considered discrepancy principles in the literature, Morozov’s method and Arcangeli’s method are widely used because of their simplicity for the purpose of applications. Although Morozov’s method and their variations have been considered extensively in the literature for general class of regularization methods, the Arcangeli’s method is known to have applied only for Tikhonov regularization. The reason could be the belief that it can never yield a rate better than Morozov’s procedure, under any smoothness assumption on the solution. However, this belief was misplaced as it has been showed by Nair (1992) that Arcangeli’s method do provide the best rate O(δ
2/3) for Tikhonov regularization under sufficient smoothness assumption on the solution, while Morozov’s method gives the rate only up to O(δ
1/2).

The purpose of this paper is to consider a generalized form of Arcangeli’s method for a general class of regularization methods for the case when there is no error on the modeling, and then extend the procedure which allow error in the modeling as well.
On an inverse source problem for the heat equation. Application to a pollution detection problem
Authors: El Badia A. , Ha-Duong T.
Published: September 2013

- We consider the problem of identification of a heat source in a bounded domain Ω. Assuming that the point sources became inactive after the time T∗, we prove that they can be identified by measurements of the heat flux on Γ0
× (0, T), where Γ0 is a part of the boundary of Ω, with non void interior, and T > T∗. By a standard trandformation, we derive from these results a method to identify the polluting sources on the surface of a river, a lake . . .
A research program in neuroimaging for an evolutionary theory of syntax
Authors: Tettamanti Marco
Published: September 2013

The Mirror System Hypothesis of Michael Arbib (2012), with respect to the cultural evolutionary origins of syntactic structure, allows to make a set of predictions about the neural mechanisms that govern the processing of modern human languages. Neuroimaging techniques may be employed to test these predictions and inform an evolutionary theory of language syntax. In this commentary, I will argue that future neuroimaging research needs in particular to: i) clarify whether linear sequential versus non-linear hierarchical structure differentially depend on mirror neurons as opposed to higher-order heteromodal cortices; ii) challenge current neuroscientific evidence on multilingualism: as it stands, syntactic processing appears to be mediated by the same neural mechanisms across languages, independently of cross-linguistic idiosyncrasies; iii) devise longitudinal studies of grammar acquisition in newborns and children; iv) recreate in the laboratory nearly-ecological conditions for the emergence of syntactic constructions through cultural and social interaction, and exploit the “experiment of nature” of pidgin and creole languages.
Archeology and the language-ready brain
Authors: Dubreuil Benoît , Henshilwood Christopher Stuart
Published: September 2013

In this book, Michael Arbib presents a most interesting and comprehensive account of the evolution of language. The work is both impressive and convincing in its description of how the language-ready brain evolved and how languages emerged through cultural evolution. As we are in broad agreement with Arbib's evolutionary story at the neurocognitive level, we focus on an underdeveloped part of his argument: when did language evolve in the human lineage? How does Arbib's neurocognitive argument connect with what archeology teaches us about human evolution?
Extraction of ursolic acid from Ocimum sanctum and synthesis of its novel derivatives: effects on extracellular homocysteine, dihydrofolate reductase activity and proliferation of HepG2 human hepatoma cells
Authors: Batra Apsara , Sastry V. Girija
Published: September 2013

The objective of the present study was to extract ursolic acid (UA) from Ocimum sanctum, to synthesize its bioactive derivatives, evaluate the anti-cancer effect of its derivatives and to establish the possible mechanism of action. In the present report, we extracted UA from whole plant of O. sanctum, synthesized its novel derivatives and investigated their effect on homocysteine metabolism and dihydrofolate reductase (DHFR) activity of HepG2 cells. UA and its derivatives UA-1, UA-2 and UA-3 down-regulated DHFR activity and increased extracellular homocysteine. UA-2 showed significant anti-proliferation activity in cancer cells. Cancer cells have increased the requirement of pyrimidine base thymidylate due to rapid cell division. Thymidylate biosynthesis depends on sufficient pools of folate dependent enzymes like DHFR. In the present study, we examined the UA and its derivatives mediated perturbation of DHFR activity and extracellular homocysteine in HepG2 human hepatoma cells. After incubation with UA-2, a potent inhibition of DHFR activity was observed. Our results showed that derivatization of UA might adversely affect DHFR activity. Measurement of extracellular homocysteine indicated impaired one-carbon metabolism in cells treated with UA derivatives. In conclusion, our data suggest an anti-cancer role of UA and its derivatives via inhibition of one-carbon metabolism.
cGMP Accumulation Causes Photoreceptor Degeneration in CNG Channel Deficiency: Evidence of cGMP Cytotoxicity Independently of Enhanced CNG Channel Function
Authors: Xu Jianhua , Morris Lynsie , Thapa Arjun , Ma Hongwei , Michalakis Stylianos , Biel Martin , Baehr Wolfgang , Peshenko Igor V. , Dizhoor Alexander M. , Ding Xi-Qin
Published: September 2013

Photoreceptor cyclic nucleotide-gated (CNG) channels regulate Ca2+influx in rod and cone photoreceptors. cGMP, the native ligand of the photoreceptor CNG channels, has been associated with cytotoxicity when its levels rise above normal due to defects in photoreceptor phosphodiesterase (PDE6) or regulation of retinal guanylyl cyclase (retGC). We found a massive accumulation of cGMP in CNGA3-deficient retina and investigated whether cGMP accumulation plays a role in cone degeneration in CNG channel deficiency. The time course study showed that the retinal cGMP level inCnga3−/−;Nrl−/−mice with CNGA3 deficiency on a cone-dominant background was sharply increased at postnatal day 8 (P8), peaked around P10–P15, remained high through P30–P60, and returned to near control level at P90. This elevation pattern correlated with photoreceptor apoptotic death, which peaked around P15–P20. InCnga3−/−;Gucy2e−/−mice lacking retGC1, cone density and expression levels of cone-specific proteins were significantly increased compared withCnga3−/−, consistent with a role of cGMP accumulation as the major contributor to cone death caused by CNG channel deficiency. The activity and expression levels of cGMP-dependent protein kinase G (PKG) were significantly increased inCnga3−/−;Nrl−/−retina compared withNrl−/−, suggesting an involvement of PKG regulation in cell death. Our results indicate that cGMP accumulation in photoreceptors can itself exert cytotoxic effect in cones, independently of CNG channel activity and Ca2+influx.
Subthalamic Nucleus Local Field Potential Activity during the Eriksen Flanker Task Reveals a Novel Role for Theta Phase during Conflict Monitoring
Authors: Zavala Baltazar , Brittain John-Stuart , Jenkinson Ned , Ashkan Keyoumars , Foltynie Thomas , Limousin Patricia , Zrinzo Ludvic , Green Alexander L. , Aziz Tipu , Zaghloul Kareem , Brown Peter
Published: September 2013

The subthalamic nucleus (STN) is thought to play a central role in modulating responses during conflict. Computational models have suggested that the location of the STN in the basal ganglia, as well as its numerous connections to conflict-related cortical structures, allows it to be ideally situated to act as a global inhibitor during conflict. Additionally, recent behavioral experiments have shown that deep brain stimulation to the STN results in impulsivity during high-conflict situations. However, the precise mechanisms that mediate the “hold-your-horses” function of the STN remain unclear. We recorded from deep brain stimulation electrodes implanted bilaterally in the STN of 13 human subjects with Parkinson's disease while they performed a flanker task. The incongruent trials with the shortest reaction times showed no behavioral or electrophysiological differences from congruent trials, suggesting that the distracter stimuli were successfully ignored. In these trials, cue-locked STN theta band activity demonstrated phase alignment across trials and was followed by a periresponse increase in theta power. In contrast, incongruent trials with longer reaction times demonstrated a relative reduction in theta phase alignment followed by higher theta power. Theta phase alignment negatively correlated with subject reaction time, and theta power positively correlated with trial reaction time. Thus, when conflicting stimuli are not properly ignored, disruption of STN theta phase alignment may help operationalize the hold-your-horses role of the nucleus, whereas later increases in the amplitude of theta oscillations may help overcome this function.
Extrasynaptic GABAAReceptors Couple Presynaptic Activity to Postsynaptic Inhibition in the Somatosensory Thalamus
Authors: Herd Murray B. , Brown Adam R. , Lambert Jeremy J. , Belelli Delia
Published: September 2013

Thalamocortical circuits govern cognitive, sensorimotor, and sleep-related network processes, and generate pathological activities during absence epilepsy. Inhibitory control of thalamocortical (TC) relay neurons is partially mediated by GABA released from neurons of the thalamic reticular nucleus (nRT), acting predominantly via synaptic α1β2γ2 GABAAreceptors (GABAARs). Importantly, TC neurons also express extrasynaptic α4β2δ GABAARs, although how they cooperate with synaptic GABAARs to influence relay cell inhibition, particularly during physiologically relevant nRT output, is unknown. To address this question, we performed paired whole-cell recordings from synaptically coupled nRT and TC neurons of the ventrobasal (VB) complex in brain slices derived from wild-type and extrasynaptic GABAAR-lacking, α4 “knock-out” (α40/0) mice. We demonstrate that the duration of VB phasic inhibition generated in response to nRT burst firing is greatly reduced in α40/0pairs, suggesting that action potential-dependent phasic inhibition is prolonged by recruitment of extrasynaptic GABAARs. Furthermore, the influence of nRT tonic firing frequency on VB holding current is also greatly reduced in α40/0pairs, implying that the α4-GABAAR-mediated tonic conductance of relay neurons is dynamically influenced, in an activity-dependent manner, by nRT tonic firing intensity. Collectively, our data reveal that extrasynaptic GABAARs of the somatosensory thalamus do not merely provide static tonic inhibition but can also be dynamically engaged to couple presynaptic activity to postsynaptic excitability. Moreover, these processes are highly sensitive to the δ-selective allosteric modulator, DS2 and manipulation of GABA transport systems, revealing novel opportunities for therapeutic intervention in thalamocortical network disorders.
Transfer of Cognitive Training across Magnitude Dimensions Achieved with Concurrent Brain Stimulation of the Parietal Lobe
Authors: Cappelletti Marinella , Gessaroli Erica , Hithersay Rosalyn , Mitolo Micaela , Didino Daniele , Kanai Ryota , Cohen Kadosh Roi , Walsh Vincent
Published: September 2013

Improvement in performance following cognitive training is known to be further enhanced when coupled with brain stimulation. Here we ask whether training-induced changes can be maintained long term and, crucially, whether they can extend to other related but untrained skills. We trained overall 40 human participants on a simple and well established paradigm assessing the ability to discriminate numerosity–or the number of items in a set–which is thought to rely on an “approximate number sense” (ANS) associated with parietal lobes. We coupled training with parietal stimulation in the form of transcranial random noise stimulation (tRNS), a noninvasive technique that modulates neural activity. This yielded significantly better and longer lasting improvement (up to 16 weeks post-training) of the precision of the ANS compared with cognitive training in absence of stimulation, stimulation in absence of cognitive training, and cognitive training coupled to stimulation to a control site (motor areas). Critically, only ANS improvement induced by parietal tRNS + Training transferred to proficiency in other parietal lobe-based quantity judgment, i.e., time and space discrimination, but not to quantity-unrelated tasks measuring attention, executive functions, and visual pattern recognition. These results indicate that coupling intensive cognitive training with tRNS to critical brain regions resulted not only in the greatest and longer lasting improvement of numerosity discrimination, but importantly in this enhancement being transferable when trained and untrained abilities are carefully chosen to share common cognitive and neuronal components.
Forebrain Deletion of the Vesicular Acetylcholine Transporter Results in Deficits in Executive Function, Metabolic, and RNA Splicing Abnormalities in the Prefrontal Cortex
Authors: Kolisnyk Benjamin , Al-Onaizi Mohammed A. , Hirata Pedro H. F. , Guzman Monica S. , Nikolova Simona , Barbash Shahar , Soreq Hermona , Bartha Robert , Prado Marco A. M. , Prado Vania F.
Published: September 2013

One of the key brain regions in cognitive processing and executive function is the prefrontal cortex (PFC), which receives cholinergic input from basal forebrain cholinergic neurons. We evaluated the contribution of synaptically released acetylcholine (ACh) to executive function by genetically targeting the vesicular acetylcholine transporter (VAChT) in the mouse forebrain. Executive function was assessed using a pairwise visual discrimination paradigm and the 5-choice serial reaction time task (5-CSRT). In the pairwise test, VAChT-deficient mice were able to learn, but were impaired in reversal learning, suggesting that these mice present cognitive inflexibility. Interestingly, VAChT-targeted mice took longer to reach criteria in the 5-CSRT. Although their performance was indistinguishable from that of control mice during low attentional demand, increased attentional demand revealed striking deficits in VAChT-deleted mice. Galantamine, a cholinesterase inhibitor used in Alzheimer's disease, significantly improved the performance of control mice, but not of VAChT-deficient mice on the 5-CSRT.In vivomagnetic resonance spectroscopy showed altered levels of two neurochemical markers of neuronal function, taurine and lactate, suggesting altered PFC metabolism in VAChT-deficient mice. The PFC of these mice displayed a drastic reduction in the splicing factor heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1), whose cholinergic-mediated reduction was previously demonstrated in Alzheimer's disease. Consequently, several key hnRNPA2/B1 target transcripts involved in neuronal function present changes in alternative splicing in VAChT-deficient mice, including pyruvate kinase M, a key enzyme involved in lactate metabolism. We propose that VAChT-targeted mice can be used to model and to dissect the neurochemical basis of executive abnormalities.
Repetition Suppression and Multi-Voxel Pattern Similarity Differentially Track Implicit and Explicit Visual Memory
Authors: Ward Emily J. , Chun Marvin M. , Kuhl Brice A.
Published: September 2013

Repeated exposure to a visual stimulus is associated with corresponding reductions in neural activity, particularly within visual cortical areas. It has been argued that this phenomenon of repetition suppression is related to increases in processing fluency or implicit memory. However, repetition of a visual stimulus can also be considered in terms of the similarity of the pattern of neural activity elicited at each exposure—a measure that has recently been linked to explicit memory. Despite the popularity of each of these measures, direct comparisons between the two have been limited, and the extent to which they differentially (or similarly) relate to behavioral measures of memory has not been clearly established. In the present study, we compared repetition suppression and pattern similarity as predictors of both implicit and explicit memory. Using functional magnetic resonance imaging, we scanned 20 participants while they viewed and categorized repeated presentations of scenes. Repetition priming (facilitated categorization across repetitions) was used as a measure of implicit memory, and subsequent scene recognition was used as a measure of explicit memory. We found that repetition priming was predicted by repetition suppression in prefrontal, parietal, and occipitotemporal regions; however, repetition priming was not predicted by pattern similarity. In contrast, subsequent explicit memory was predicted by pattern similarity (across repetitions) in some of the same occipitotemporal regions that exhibited a relationship between priming and repetition suppression; however, explicit memory was not related to repetition suppression. This striking double dissociation indicates that repetition suppression and pattern similarity differentially track implicit and explicit learning.
Neutrophils Express Oncomodulin and Promote Optic Nerve Regeneration
Authors: Kurimoto Takuji , Yin Yuqin , Habboub Ghaith , Gilbert Hui-Ya , Li Yiqing , Nakao Shintaro , Hafezi-Moghadam Ali , Benowitz Larry I.
Published: September 2013

Although neurons are normally unable to regenerate their axons after injury to the CNS, this situation can be partially reversed by activating the innate immune system. In a widely studied instance of this phenomenon, proinflammatory agents have been shown to cause retinal ganglion cells, the projection neurons of the eye, to regenerate lengthy axons through the injured optic nerve. However, the role of different molecules and cell populations in mediating this phenomenon remains unclear. We show here that neutrophils, the first responders of the innate immune system, play a central role in inflammation-induced regeneration. Numerous neutrophils enter the mouse eye within a few hours of inducing an inflammatory reaction and express high levels of the atypical growth factor oncomodulin (Ocm). Immunodepletion of neutrophils diminished Ocm levels in the eye without altering levels of CNTF, leukemia inhibitory factor, or IL-6, and suppressed the proregenerative effects of inflammation. A peptide antagonist of Ocm suppressed regeneration as effectively as neutrophil depletion. Macrophages enter the eye later in the inflammatory process but appear to be insufficient to stimulate extensive regeneration in the absence of neutrophils. These data provide the first evidence that neutrophils are a major source of Ocm and can promote axon regeneration in the CNS.
Learning from the LA Aqueduct
Authors: Hiltzik Michael
Published: September 2013

This article considers major infrastructure spending projects on the table in California (a high-speed rail line connecting Los Angeles to San Francisco, a peripheral canal in the Sacramento Delta, higher education) and compares their funding models to that of the Los Angeles Aqueducts. Whereas William Mulholland convinced Angelenos in 1905 to pay for the aqueduct for the benefit of future residents, modern California voters are more likely to insist infrastructure is paid for with a mix of public and private investment, or solely by its end users. Hiltzik argues California’s leaders could learn from Mulholland, whose foresight, adept campaigning, and willingness to shade the truth benefited millions of people.
Owens Valley and the Public Trust
Authors: Chisholm Graham
Published: September 2013

This essay explores the history of the public trust doctrine for water in California, established in the battle of preserving Mono Lake, and extends the concept to include the responsibility Los Angeles has to restore Owens Lake, an important habitat for migratory birds.
Aromatase activity induction in human adipose fibroblasts by retinoic acids via retinoic acid receptor α
Authors: Wilde Jan , Erdmann Maria , Mertens Michael , Eiselt Gabriele , Schmidt Martin
Published: September 2013

Estrogen synthesis in adipose tissue is associated with the development of breast cancer. Tumors are preferentially found in breast quadrants with strongest expression of the cytochrome P450 aromatase (encoded by the geneCYP19A1). Several promoters regulated by various hormonal factors drive aromatase expression in human breast adipose fibroblasts (BAFs). As adipose tissue is a major source of retinoids, in this study, we investigated their role in the regulation of aromatase expression. The retinoids all-trans-retinoic acid (at-RA) and 9-cis-RA induce aromatase activity in human BAFs. In BAFs, at-RA induces aromatase gene expression via promoter I.4. In 3T3-L1 cells, both retinoids specifically drive luciferase reporter gene expression under the control of aromatase promoter I.4, whereas other promoters active in human adipose tissue are insensitive. Activation by retinoids depends on a 467 bp fragment (−256/+211) of promoter I.4 containing four putative retinoic acid response elements (RAREs). Site-directed mutagenesis revealed that only RARE2 (+91/+105) mediates the retinoid-dependent induction of reporter gene activity. In 3T3-L1 preadipocytes and human BAFs, RA receptor α (RARα (RARA)) expression is predominant, whereas RARβ (RARB) or RARγ (RARG) expression is low. Electrophoretic mobility shift assays with nuclear extracts obtained from human BAFs and 3T3-L1 cells identified a specific RARE2-binding complex. Retinoids enhanced complex formation, whereas pre-incubation with anti-RARα antibodies prohibited the binding of RARα to RARE2. Chromatin immunoprecipitation showed RA-dependent binding of RARα to the RARE2-containing promoter regionin vivo. Furthermore, we provide evidence that RARE2 is also necessary for the basal activation of promoter I.4 in these cells. Taken together, these findings indicate a novel retinoid-dependent mechanism of aromatase activity induction in adipose tissue.