bluuebunny/crossref_metadata_2025 huggingface dataset:
The relationship between transcription initiation RNAs and CCCTC-binding factor (CTCF) localization
Authors: Taft Ryan J , Hawkins Peter G , Mattick John S , Morris Kevin V
Published: August 2011

Background

Transcription initiation RNAs (tiRNAs) are nuclear localized 18 nucleotide RNAs derived from sequences immediately downstream of RNA polymerase II (RNAPII) transcription start sites. Previous reports have shown that tiRNAs are intimately correlated with gene expression, RNA polymerase II binding and behaviors, and epigenetic marks associated with transcription initiation, but not elongation.

Results

In the present work, we show that tiRNAs are commonly found at genomic CCCTC-binding factor (CTCF) binding sites in human and mouse, and that CTCF sites that colocalize with RNAPII are highly enriched for tiRNAs. To directly investigate the relationship between tiRNAs and CTCF we examined tiRNAs originating near the intronic CTCF binding site in the human tumor suppressor gene, p21 (cyclin-dependent kinase inhibitor 1A gene, also known as CDKN1A). Inhibition of CTCF-proximal tiRNAs resulted in increased CTCF localization and increased p21 expression, while overexpression of CTCF-proximal tiRNA mimics decreased CTCF localization and p21 expression. We also found that tiRNA-regulated CTCF binding influences the levels of trimethylated H3K27 at the alternate upstream p21 promoter, and affects the levels of alternate p21 (p21

alt
) transcripts. Extending these studies to another randomly selected locus with conserved CTCF binding we found that depletion of tiRNA alters nucleosome density proximal to sites of tiRNA biogenesis.

Conclusions

Taken together, these data suggest that tiRNAs modulate local epigenetic structure, which in turn regulates CTCF localization.
Positive spill‐over effects of ART scale up on wider health systems development: evidence from Ethiopia and Malawi
Authors: Rasschaert Freya , Pirard Marjan , Philips Mit P , Atun Rifat , Wouters Edwin , Assefa Yibeltal , Criel Bart , Schouten Erik J , Van Damme Wim
Published: August 2011

Background

Global health initiatives have enabled the scale up of antiretroviral treatment (ART) over recent years. The impact of HIV‐specific funds and programmes on non‐HIV‐related health services and health systems in genera has been debated extensively. Drawing on evidence from Malawi and Ethiopia, this article analyses the effects of ART scale‐up interventions on human resources policies, service delivery and general health outcomes, and explores how synergies can be maximized.

Methods

Data from Malawi and Ethiopia were compiled between 2004 and 2009 and between 2005 and 2009, respectively. We developed a conceptual health systems framework for the analysis. We used the major changes in human resources policies as an entry point to explore the wider health systems changes.

Results

In both countries, the need for an HIV response triggered an overhaul of human resources policies. As a result, the health workforce at health facility and community level was reinforced. The impact of this human resources trend was felt beyond the scale up of ART services; it also contributed to an overall increase in functional health facilities providing curative, mother and child health, and ART services. In addition to a significant increase in ART coverage, we observed a remarkable rise in user rates of non‐HIV health services and an improvement in overall health outcomes.

Conclusions

Interventions aimed at the expansion of ART services and improvement of long‐term retention of patients in ART care can have positive spill‐over effects on the health system. The responses of Malawi and Ethiopia to their human resources crises was exceptional in many respects, and some of the lessons learnt can be useful in other contexts. The case studies show the feasibility of obtaining improved health outcomes beyond HIV through scaled‐up ART interventions when these are part of a long‐term, system‐wide health plan supported by all decision makers and funders.
Multicentre validation of the bedside paediatric early warning system score: a severity of illness score to detect evolving critical illness in hospitalised children
Authors: Parshuram Christopher S , Duncan Heather P , Joffe Ari R , Farrell Catherine A , Lacroix Jacques R , Middaugh Kristen L , Hutchison James S , Wensley David , Blanchard Nadeene , Beyene Joseph , Parkin Patricia C
Published: August 2011

Introduction

The timely provision of critical care to hospitalised patients at risk for cardiopulmonary arrest is contingent upon identification and referral by frontline providers. Current approaches require improvement. In a single-centre study, we developed the Bedside Paediatric Early Warning System (Bedside PEWS) score to identify patients at risk. The objective of this study was to validate the Bedside PEWS score in a large patient population at multiple hospitals.

Methods

We performed an international, multicentre, case-control study of children admitted to hospital inpatient units with no limitations on care. Case patients had experienced a clinical deterioration event involving either an immediate call to a resuscitation team or urgent admission to a paediatric intensive care unit. Control patients had no events. The scores ranged from 0 to 26 and were assessed in the 24 hours prior to the clinical deterioration event. Score performance was assessed using the area under the receiver operating characteristic (AUCROC) curve by comparison with the retrospective rating of nurses and the temporal progression of scores in case patients.

Results

A total of 2,074 patients were evaluated at 4 participating hospitals. The median (interquartile range) maximum Bedside PEWS scores for the 12 hours ending 1 hour before the clinical deterioration event were 8 (5 to 12) in case patients and 2 (1 to 4) in control patients (P < 0.0001). The AUCROC curve (95% confidence interval) was 0.87 (0.85 to 0.89). In case patients, mean scores were 5.3 at 20 to 24 hours and 8.4 at 0 to 4 hours before the event (P < 0.0001). The AUCROC curve (95% CI) of the retrospective nurse ratings was 0.83 (0.81 to 0.86). This was significantly lower than that of the Bedside PEWS score (P < 0.0001).

Conclusions

The Bedside PEWS score identified children at risk for cardiopulmonary arrest. Scores were elevated and continued to increase in the 24 hours before the clinical deterioration event. Prospective clinical evaluation is needed to determine whether this score will improve the quality of care and patient outcomes.
Bortezomib Added to R-CVP Is Safe and Effective for Previously Untreated Advanced-Stage Follicular Lymphoma: A Phase II Study by the National Cancer Institute of Canada Clinical Trials Group
Authors: Sehn Laurie H. , MacDonald David , Rubin Sheldon , Cantin Guy , Rubinger Morel , Lemieux Bernard , Basi Sanraj , Imrie Kevin , Gascoyne Randy D. , Sussman Jonathan , Chen Bingshu E. , Djurfeldt Marina , Shepherd Lois , Couban Stephen , Crump Michael
Published: August 2011

Purpose

Bortezomib has demonstrated promising activity in patients with follicular lymphoma (FL). This is the first study to evaluate the safety and efficacy of bortezomib added to rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) in previously untreated advanced-stage FL.

Patients and Methods

This is a phase II multicenter trial adding bortezomib (1.3 mg/m2 days 1 and 8) to standard-dose R-CVP (BR-CVP) for up to eight cycles in patients with newly diagnosed stage III/IV FL requiring therapy. Two co-primary end points, complete response rate (complete response [CR]/CR unconfirmed [CRu]) and incidence of grade 3 or 4 neurotoxicity, were assessed.

Results

Between December 2006 and March 2009, 94 patients were treated with BR-CVP. Median patient age was 57 years (range, 29 to 84 years), and the majority had a high (47%) or intermediate (43%) Follicular Lymphoma International Prognostic Index score. BR-CVP was extremely well tolerated, with 90% of patients completing the intended eight cycles. No patients developed grade 4 neurotoxicity, and only five of 94 patients (5%; 95% CI, 0.8% to 9.9%) developed grade 3 neurotoxicity, which was largely reversible. On the basis of an intention-to-treat analysis, 46 of 94 patients (49%; 95% CI, 38.8% to 59.0%) achieved a CR/CRu, and 32 of 94 patients (34%) achieved a partial response, for an overall response rate of 83% (95% CI, 75.4% to 90.6%).

Conclusion

The addition of bortezomib to standard-dose R-CVP for advanced-stage FL is feasible and well tolerated with minimal additional toxicity. The complete response rate in this high-risk population compares favorably to historical results of patients receiving R-CVP. Given these results, a phase III trial comparing BR-CVP with R-CVP is planned.
Phase III Study of Molecularly Targeted Adjuvant Therapy in Locally Advanced Urothelial Cancer of the Bladder Based on p53 Status
Authors: Stadler Walter M. , Lerner Seth P. , Groshen Susan , Stein John P. , Shi Shan-Rong , Raghavan Derek , Esrig David , Steinberg Gary , Wood David , Klotz Laurence , Hall Craig , Skinner Donald G. , Cote Richard J.
Published: August 2011

Introduction

Retrospective studies suggest that p53 alteration is prognostic for recurrence in patients with urothelial bladder cancer and predictive for benefit from combination methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) adjuvant chemotherapy.

Patients and Methods

Patients with pT1/T2N0M0 disease whose tumors demonstrated ≥ 10% nuclear reactivity on centrally performed immunohistochemistry for p53 were offered random assignment to three cycles of adjuvant MVAC versus observation; p53-negative patients were observed. By using a log-rank test with one-sided α = .05 and β = .10, 190 p53-positive patients were planned to be randomly assigned to detect an absolute improvement in probability of recurring by 3 years from 0.50 to 0.30.

Results

A total of 521 patients were registered, 499 underwent p53 assessment, 272 (55%) were positive, and 114 (42%) were randomly assigned. Accrual was halted on the basis of the data and safety monitoring board review of a futility analysis. Overall 5-year probability of recurring was 0.20 (95% CI, 0.16 to 0.24) with no difference on the basis of p53 status. Only 67% of patients randomly assigned to MVAC received all three cycles with 12 patients receiving no treatment. There was no difference in recurrence in the randomly assigned patients (hazard ratio, 0.78; 95% CI, 0.29 to 2.08; P = .62).

Conclusion

Neither the prognostic value of p53 nor the benefit of MVAC chemotherapy in patients with p53-positive tumors was confirmed, but the high patient refusal rate, lower than expected event rate, and failures to receive assigned therapy severely compromised study power.
High Incidence of Thromboembolic Events in Patients Treated With Cisplatin-Based Chemotherapy: A Large Retrospective Analysis
Authors: Moore Russell A. , Adel Nelly , Riedel Elyn , Bhutani Manisha , Feldman Darren R. , Tabbara Nour Elise , Soff Gerald , Parameswaran Rekha , Hassoun Hani
Published: August 2011

Purpose

This study was designed to determine the incidence of venous and arterial thromboembolic events (TEEs) in patients treated with cisplatin-based chemotherapy and to analyze the prognostic value of patients' baseline and treatment characteristics in predicting TEE occurrence.

Patients and Methods

We performed a large retrospective analysis of all patients treated with cisplatin-based chemotherapy for any type of malignancy at Memorial Sloan-Kettering Cancer Center in 2008. A TEE was cisplatin-associated if it occurred between the time of the first dose of cisplatin and 4 weeks after the last dose.

Results

Among 932 patients, 169 (18.1%) experienced a TEE during treatment or within 4 weeks of the last dose. TEEs included deep vein thrombosis (DVT) alone in 49.7%, pulmonary embolus (PE) alone in 25.4%, DVT plus PE in 13.6%, arterial TEE alone in 8.3%, or DVT plus arterial TEE in 3.0%. TEEs occurred within 100 days of initiation of treatment in 88% of patients. By univariate analysis, sex, age, race, Karnofsky performance status (KPS), exposure to erythropoiesis-stimulating agents, presence of central venous catheter (CVC), site of cancer, stage of cancer, leukocyte and hemoglobin levels, and Khorana score were all identified as risk factors. However, by multivariate analysis, only age, KPS, presence of CVC, and Khorana score retained significance.

Conclusion

This large retrospective analysis confirms the unacceptable incidence of TEEs in patients receiving cisplatin-based chemotherapy. In view of the controversy associated with prophylactic anticoagulation in patients with cancer treated with chemotherapy, randomized studies are urgently needed in this specific cancer population treated with cisplatin-based regimens.
Hyperinsulinemia Induces Insulin Resistance in Dorsal Root Ganglion Neurons
Authors: Kim Bhumsoo , McLean Lisa L. , Philip Stephen S. , Feldman Eva L.
Published: August 2011

Insulin resistance (IR) is the major feature of metabolic syndrome, including type 2 diabetes. IR studies are mainly focused on peripheral tissues, such as muscle and liver. There is, however, little knowledge about IR in neurons. In this study, we examined whether neurons develop IR in response to hyperinsulinemia. We first examined insulin signaling using adult dorsal root ganglion neurons as a model system. Acute insulin treatment resulted in time- and concentration-dependent activation of the signaling cascade, including phosphorylation of the insulin receptor, Akt, p70S6K, and glycogen synthase kinase-3β. To mimic hyperinsulinemia, cells were pretreated with 20 nm insulin for 24 h and then stimulated with 20 nm insulin for 15 min. Chronic insulin treatment resulted in increased basal Akt phosphorylation. More importantly, acute insulin stimulation after chronic insulin treatment resulted in blunted phosphorylation of Akt, p70S6K, and glycogen synthase kinase-3β. Interestingly, when the cells were treated with phosphatidylinositol 3-kinase pathway inhibitor, but not MAPK pathway inhibitor, chronic insulin treatment did not block acute insulin treatment-induced Akt phosphorylation. Insulin-induced Akt phosphorylation was lower in dorsal root ganglion neurons from BKS-db/db compared with control BKS-db+ mice. This effect was age dependent. Our results suggest that hyperinsulinemia cause IR by disrupting the Akt-mediated pathway. We also demonstrate that hyperinsulinemia increases the mitochondrial fission protein dynamin-related protein 1. Our results suggest a new theory for the etiology of diabetic neuropathy, i.e. that, similar to insulin dependent tissues, neurons develop IR and, in turn, cannot respond to the neurotrophic properties of insulin, resulting in neuronal injury and the development of neuropathy.
Definitions of terms relating to crystalline polymers (IUPAC Recommendations 2011)
Authors: Meille Stefano V. , Allegra Giuseppe , Geil Phillip H. , He Jiasong , Hess Michael , Jin Jung-Il , Kratochvíl Pavel , Mormann Werner , Stepto Robert
Published: August 2011

Recommendations are given concerning the terminology relating to the structure and the morphology of crystalline polymers and the processes of polymer crystallization. They are applicable to cases where polymer crystals are a significant fraction of a system and primarily with crystal structures that are comprised of polymer chains with limited, static, or dynamic disorder. After some general definitions, terms pertaining to structural arrangements at subnanometric scales and to polymer crystal structures are defined. Terms relating to molecular conformation within polymer crystals, morphological aspects, and polymer crystallization are given in subsequent sections.
Die Argumentation des Patriarchen Gregorios II. Kyprios zur Widerlegung des Filioque-Ansatzes in der Schrift. De processione Spiritus sancti
Authors: Alexopoulos Theodoros
Published: August 2011

Focussing on the thirteenth-century endings of Byzantine writings against the Latin innovation of the Filioque, the present study aims, on the basis of the work De processione Spiritus sancti (1283), to provide the reader with an insight into the nature of the Orthodox argumentation refuting the Filioque. The work was until now attributed to Gregorios Kyprios Patriarch of Konstantinople (1283–1289). However, it is not a product of his pen, but a compiled version of his earlier work, the “Antirrheticos against Bekkos”. Throughout the study the writer follows step by step Kyprios' reasoning and tries to control the validity and soundness of the arguments advanced, making at the same time specific references to the patristic and philosophical background of Kyprios' thinking. The study shows beyond any doubt that Kyprios is indebted to his predecessors, mostly to the Cappadocians and Dionysius Areopagites, and that he argues on the same line of reasoning with them in respect to the idea of the “Monarchy” of the Father, of the incommunicable of hypostatic properties, and of the possibility of beings to be in communion with God only through the divine energies. On the ground of these three fundamental ideas, a procession of the Spirit also from the Son is categorically rejected. Only the mission of the Spirit (what is implied here, are the gifts of the Spirit and not the Spirit itself) into the world through the Son is acceptable.
The integral cohomology of configuration spaces of pairs of points in real projective spaces
Authors: Domínguez Carlos , González Jesús , Landweber Peter
Published: August 2011

We compute the integral cohomology ring of configuration spaces of two points on a given real projective space. Apart from an integral class, the resulting ring is a quotient of the known integral cohomology of the dihedral group of order 8 (in the case of unordered configurations, thus has only 2- and 4-torsion) or of the elementary abelian
2-group of rank 2 (in the case of ordered configurations, thus has only 2-torsion). As an application, we complete the computation of the symmetric topological complexity of real projective
spaces with and .
Temporal Precision in the Visual Pathway through the Interplay of Excitation and Stimulus-Driven Suppression
Authors: Butts Daniel A. , Weng Chong , Jin Jianzhong , Alonso Jose-Manuel , Paninski Liam
Published: August 2011

Visual neurons can respond with extremely precise temporal patterning to visual stimuli that change on much slower time scales. Here, we investigate how the precise timing of cat thalamic spike trains—which can have timing as precise as 1 ms—is related to the stimulus, in the context of both artificial noise and natural visual stimuli. Using a nonlinear modeling framework applied to extracellular data, we demonstrate that the precise timing of thalamic spike trains can be explained by the interplay between an excitatory input and a delayed suppressive input that resembles inhibition, such that neuronal responses only occur in brief windows where excitation exceeds suppression. The resulting description of thalamic computation resembles earlier models of contrast adaptation, suggesting a more general role for mechanisms of contrast adaptation in visual processing. Thus, we describe a more complex computation underlying thalamic responses to artificial and natural stimuli that has implications for understanding how visual information is represented in the early stages of visual processing.
DrosophilaQVR/SSS Modulates the Activation and C-Type Inactivation Kinetics of Shaker K+Channels
Authors: Dean Terry , Xu Rong , Joiner William , Sehgal Amita , Hoshi Toshinori
Published: August 2011

Thequiver/sleepless(qvr/sss) gene encodes a small, glycosylphosphatidylinositol-anchored protein that plays a critical role in the regulation of sleep inDrosophila. Loss-of-function mutations inqvr/sssseverely suppress sleep and effect multiple changes inin situShaker K+currents, including decreased magnitude, slower time-to-peak, and cumulative inactivation. Recently, we demonstrated that SLEEPLESS (SSS) protein modulates Shaker channel activity, possibly through a direct interaction at the plasma membrane. We show here that SSS accelerates the activation of heterologously expressed Shaker channels with no effect on deactivation or fast N-type inactivation. Furthermore, this SSS-induced acceleration is sensitive to the pharmacological disruption of lipid rafts and sufficiently accounts for the slower time-to-peak ofin situShaker currents seen inqvr/sssmutants. We also find that SSS decreases the rate of C-type inactivation of heterologously expressed Shaker channels, providing a potential mechanism for the cumulative inactivation phenotype induced byqvr/sssloss-of-function mutations. Kinetic modeling based on thein vitroresults suggests that the SSS-dependent regulation of channel kinetics accounts for nearly 40% of the decrease in Shaker current magnitude in flies lacking SSS. Sleep duration inqvr/sss-null mutants is restored to normal by aqvr/ssstransgene that fully rescues the Shaker kinetic phenotypes but only partially rescues the decrease in current magnitude. Together, these results suggest that the role of SSS in the regulation of sleep inDrosophilacorrelates more strongly with the effects of SSS on Shaker kinetics than current magnitude.
Visual-Induced Excitation Leads to Firing Pauses in Striatal Cholinergic Interneurons
Authors: Schulz Jan M. , Oswald Manfred J. , Reynolds John N. J.
Published: August 2011

Tonically active neurons in the primate striatum, believed to be cholinergic interneurons (CINs), respond to sensory stimuli with a pronounced pause in firing. Although inhibitory and neuromodulatory mechanisms have been implicated, it is not known how sensory stimuli induce firing pauses in CINsin vivo. Here, we used intracellular recordings in anesthetized rats to investigate the effectiveness of a visual stimulus at modulating spike activity in CINs. Initially, no neuron was visually responsive. However, following pharmacological activation of tecto-thalamic pathways, the firing pattern of most CINs was significantly modulated by a light flashed into the contralateral eye. Typically, this induced an excitation followed by a pause in spike firing, via an underlying depolarization–hyperpolarization membrane sequence. Stimulation of thalamic afferentsin vitroevoked similar responses that were independent of synaptic inhibition. Thus, visual stimulation likely induces an initial depolarization via a subcortical tecto-thalamo-striatal pathway, pausing CIN firing through an intrinsic afterhyperpolarization.
Augmented Cocaine Seeking in Response to Stress or CRF Delivered into the Ventral Tegmental Area Following Long-Access Self-Administration Is Mediated by CRF Receptor Type 1 But Not CRF Receptor Type 2
Authors: Blacktop Jordan M. , Seubert Chad , Baker David A. , Ferda Nathan , Lee Geng , Graf Evan N. , Mantsch John R.
Published: August 2011

Stressful events are determinants of relapse in recovering cocaine addicts. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) regulation of neurocircuitry involved in drug seeking. We previously reported that the reinstatement of cocaine seeking by a stressor (footshock) is CRF dependent and is augmented in rats that self-administered cocaine under long-access (LgA; 6 h daily) conditions for 14 d when compared with rats provided shorter daily cocaine access [short access (ShA) rats; 2 h daily]. Further, we have demonstrated that reinstatement in response to intracerebroventricular CRF administration is heightened in LgA rats. This study examined the role of altered ventral tegmental area (VTA) responsiveness to CRF in intake-dependent increases in CRF- and stress-induced cocaine seeking. Bilateral intra-VTA administration of CRF (250 or 500 ng/side) produced reinstatement in LgA but not ShA rats. In LgA rats, intra-VTA CRF-induced reinstatement was blocked by administration of the CRF-receptor type 1 (CRF-R1) antagonist antalarmin (500 ng/side) or CP-376395 (500 ng/side), but not the CRF-R2 antagonist astressin-2B (500 ng or 1 μg/side) or antisauvagine-30 (ASV-30; 500 ng/side) into the VTA. Likewise, intra-VTA antalarmin, but not astressin-2B, blocked footshock-induced reinstatement in LgA rats. By contrast, neither intra-VTA antalarmin nor CP-376395 altered food-reinforced lever pressing. Intra-VTA injection of the CRF-R1-selective agonist cortagine (100 ng/side) but not the CRF-R2-selective agonist rat urocortin II (rUCN II; 250 ng/side) produced reinstatement. These findings reveal that excessive cocaine use increases susceptibility to stressor-induced relapse in part by augmenting CRF-R1-dependent regulation of addiction-related neurocircuitry in the VTA.
Two Transcription Factors Can Direct Three Photoreceptor Outcomes from Rod Precursor Cells in Mouse Retinal Development
Authors: Ng Lily , Lu Ailing , Swaroop Alok , Sharlin David S. , Swaroop Anand , Forrest Douglas
Published: August 2011

The typical mammalian visual system is based upon three photoreceptor types: rods for dim light vision and two types of cones (M and S) for color vision in daylight. However, the process that generates photoreceptor diversity and the cell type in which diversity arises remain unclear. Mice deleted for thyroid hormone receptor β2 (TRβ2) and neural retina leucine zipper factor (NRL) lack M cones and rods, respectively, but gain S cones. We therefore tested the hypothesis that NRL and TRβ2 direct a common precursor to a rod, M cone, or S cone outcome usingNrlb2/b2“knock-in” mice that express TRβ2 instead of NRL from the endogenousNrlgene.Nrlb2/b2mice lacked rods and produced excess M cones in contrast to the excess S cones inNrl−/−mice. Notably, the presence of both factors yielded rods inNrl+/b2mice. The results demonstrate innate plasticity in postmitotic rod precursors that allows these cells to form three functional photoreceptor types in response to NRL or TRβ2. We also detected precursor cells in normal embryonic retina that transiently coexpressedNrland TRβ2, suggesting that some precursors may originate in a plastic state. The plasticity of the precursors revealed inNrlb2/b2mice suggests that a two-step transcriptional switch can direct three photoreceptor fates: first, rod versus cone identity dictated by NRL, and second, if NRL fails to act, M versus S cone identity dictated by TRβ2.
Repeated Amphetamine Exposure Disrupts Dopaminergic Modulation of Amygdala–Prefrontal Circuitry and Cognitive/Emotional Functioning
Authors: Tse Maric T. L. , Cantor Anna , Floresco Stan B.
Published: August 2011

Repeated exposure to psychostimulants such as amphetamine (AMPH) disrupts cognitive and behavioral processes mediated by the medial prefrontal cortical (mPFC) and basolateral amygdala (BLA). The present study investigated the effects of repeated AMPH exposure on the neuromodulatory actions of dopamine (DA) on BLA–mPFC circuitry and cognitive/emotional processing mediated by these circuits. Rats received five AMPH (2 mg/kg) or saline injections (controls) over 10 d, followed by 2–4 week drug washout.In vivoneurophysiological extracellular recordings in urethane-anesthetized rats were used to obtain data from mPFC neurons that were either inhibited or excited by BLA stimulation. In controls, acute AMPH attenuated BLA-evoked inhibitory or excitatory responses; these effects were mimicked by selective D2or D1agonists, respectively. However, in AMPH-treated rats, the ability of these dopaminergic manipulations to modulate BLA-driven decreases/increases in mPFC activity was abolished. Repeated AMPH also blunted the excitatory effects of ventral tegmental area stimulation on mPFC neural firing. Behavioral studies assessed the effect of repeated AMPH on decision making with conditioned punishment, a process mediated by BLA–mPFC circuitry and mesocortical DA. These treatments impaired the ability of rats to use conditioned aversive stimuli (footshock-associated cue) to guide the direction of instrumental responding. Collectively, these data suggest that repeated AMPH exposure can lead to persistent disruption of dopaminergic modulation of BLA–mPFC circuitry, which may underlie impairments in cognitive/emotional processing observed in stimulant abusers. Furthermore, they suggest that impairments in decision making guided by aversive stimuli observed in stimulant abusers may be the result of repeated drug exposure.
Inflammation-Induced Lethargy Is Mediated by Suppression of Orexin Neuron Activity
Authors: Grossberg Aaron J. , Zhu XinXia , Leinninger Gina M. , Levasseur Peter R. , Braun Theodore P. , Myers Martin G. , Marks Daniel L.
Published: August 2011

In response to illness, animals subvert normal homeostasis and divert their energy utilization to fight infection. An important and unexplored feature of this response is the suppression of physical activity and foraging behavior in the setting of negative energy balance. Inflammatory signaling in the hypothalamus mediates the febrile and anorectic responses to disease, but the mechanism by which locomotor activity (LMA) is suppressed has not been described. Lateral hypothalamic orexin (Ox) neurons link energy status with LMA, and deficiencies in Ox signaling lead to hypoactivity and hypophagia. In the present work, we examine the effect of endotoxin-induced inflammation on Ox neuron biology and LMA in rats. Our results demonstrate a vital role for diminished Ox signaling in mediating inflammation-induced lethargy. This work defines a specific population of inflammation-sensitive, arousal-associated Ox neurons and identifies a proximal neural target for inflammatory signaling to Ox neurons, while eliminating several others.
Distinct and Non-Redundant Roles of Microglia and Myeloid Subsets in Mouse Models of Alzheimer's Disease
Authors: Mildner Alexander , Schlevogt Bernhard , Kierdorf Katrin , Böttcher Chotima , Erny Daniel , Kummer Markus P. , Quinn Michael , Brück Wolfgang , Bechmann Ingo , Heneka Michael T. , Priller Josef , Prinz Marco
Published: August 2011

Mononuclear phagocytes are important modulators of Alzheimer's disease (AD), but the specific functions of resident microglia, bone marrow-derived mononuclear cells, and perivascular macrophages have not been resolved. To elucidate the spatiotemporal roles of mononuclear phagocytes during disease, we targeted myeloid cell subsets from different compartments and examined disease pathogenesis in three different mouse models of AD (APPswe/PS1,APPswe, andAPP23mice). We identified chemokine receptor 2 (CCR2)-expressing myeloid cells as the population that was preferentially recruited to β-amyloid (Aβ) deposits. Unexpectedly, AD brains with dysfunctional microglia and devoid of parenchymal bone marrow-derived phagocytes did not show overt changes in plaque pathology and Aβ load. In contrast, restriction of CCR2 deficiency to perivascular myeloid cells drastically impaired β-amyloid clearance and amplified vascular Aβ deposition, while parenchymal plaque deposition remained unaffected. Together, our data advocate selective functions of CCR2-expressing myeloid subsets, which could be targeted specifically to modify disease burden in AD.
Physical and Perceptual Factors Shape the Neural Mechanisms That Integrate Audiovisual Signals in Speech Comprehension
Authors: Lee HweeLing , Noppeney Uta
Published: August 2011

Face-to-face communication challenges the human brain to integrate information from auditory and visual senses with linguistic representations. Yet the role of bottom-up physical (spectrotemporal structure) input and top-down linguistic constraints in shaping the neural mechanisms specialized for integrating audiovisual speech signals are currently unknown. Participants were presented with speech and sinewave speech analogs in visual, auditory, and audiovisual modalities. Before the fMRI study, they were trained to perceive physically identical sinewave speech analogs as speech (SWS-S) or nonspeech (SWS-N). Comparing audiovisual integration (interactions) of speech, SWS-S, and SWS-N revealed a posterior–anterior processing gradient within the left superior temporal sulcus/gyrus (STS/STG): Bilateral posterior STS/STG integrated audiovisual inputs regardless of spectrotemporal structure or speech percept; in left mid-STS, the integration profile was primarily determined by the spectrotemporal structure of the signals; more anterior STS regions discarded spectrotemporal structure and integrated audiovisual signals constrained by stimulus intelligibility and the availability of linguistic representations. In addition to this “ventral” processing stream, a “dorsal” circuitry encompassing posterior STS/STG and left inferior frontal gyrus differentially integrated audiovisual speech and SWS signals. Indeed, dynamic causal modeling and Bayesian model comparison provided strong evidence for a parallel processing structure encompassing a ventral and a dorsal stream with speech intelligibility training enhancing the connectivity between posterior and anterior STS/STG. In conclusion, audiovisual speech comprehension emerges in an interactive process with the integration of auditory and visual signals being progressively constrained by stimulus intelligibility along the STS and spectrotemporal structure in a dorsal fronto-temporal circuitry.
Heritability of the risk factors characteristic for the metabolic syndrome: a twin study
Authors: Jermendy György , Littvay Levente , Steinbach Rita , Jermendy Ádám , Tárnoki Ádám , Tárnoki Dávid , Métneki Júlia , Osztovits János
Published: August 2011

Both genetic and environmental factors play role in the pathogenesis of the metabolic syndrome. The magnitude of genetic and environmental influences on the components of metabolic syndrome may vary in different populations. Aims: The present study was aimed to determine the effects of genetic and environmental factors on risk factors characteristic for the metabolic syndrome. Methods: A total of 101 (63 monozygotic and 38 dizygotic) adult twin pairs (n = 202; mean age: 43.3±15.8 years) were investigated. Medical history was recorded and physical examination was carried out for each subject. Fasting venous blood samples were used for measuring laboratory parameters. The presented estimates include the heritability structural equation (A-C-E) model results. In Model-1, all presented parameters are age- and gender- corrected. In Model-2, parameters were corrected for age, gender, body mass index and waist circumference. Results: Heritability in waist circumference (as well as in other anthropometric parameters such as weight and height) was high (Model-1: 71.0–88.1%). Similarly, genetic factors had the highest proportion of total phenotypic variance in systolic and diastolic blood pressure (Model-2: 57.1% and 57.7%, respectively). Based on the results of Model-2, unique environmental factors dominate alterations in serum triglycerides values (55.9%) while shared environmental factors proved to be substantial in alterations of HDL-cholesterol and fasting blood glucose values (58.1% and 57.1%, respectively). Comparing the results of Model-1 and Model-2, the difference in A-C-E model varied from 0.0% to 17.1%, indicating that only a minor proportion of genetic and environmental influences can be explained by the effects of anthropometric parameters. Conclusions: Among adult Hungarian healthy people, genetic factors have substantial influence on waist circumference and blood pressure values while environmental factors dominate alterations in serum triglycerides, HDL-cholesterol and fasting blood glucose values. The different heritability of individual risk factors challenges the original unifying concept of the metabolic syndrome. The results may be useful for establishing and implementing primary cardiovascular prevention both at individual and population levels. Orv. Hetil., 2011, 152, 1265–1271.
Perennial Ryegrass (Lolium perenne L.) and Grooming Affect Bermudagrass Traffic Tolerance
Authors: Thoms Adam W. , Sorochan John C. , Brosnan James T. , Samples Thomas J.
Published: August 2011

Data describing intraspecific differences in hybrid bermudagrass [Cynodon dactylon (L.) Pers. × C. transvaalensis Burtt Davy] traffic tolerance are limited. Field research was conducted evaluating the effects of mowing practices and perennial ryegrass (Lolium perenne L.) overseeding on the traffic tolerance of three hybrid and one improved common bermudagrass. Bermudagrass cultivars (‘Tifway’, ‘Patriot’, ‘Mississippi Choice’, and ‘Riviera’) were subjected to mowing programs (reel mowing at 2.2 cm [RM] or RM plus grooming to a 1.9 cm depth [RMPG]) and perennial ryegrass overseeding (0 kg pure live seed [PLS] ha−1 or 593 kg PLS ha−1). Simulated traffic was applied twice weekly with a Cady traffic simulator. Percent green cover was measured after each simulated traffic event using digital image analysis. On >70% of evaluation dates, Tifway and Riviera yielded higher percent green cover compared to Patriot, while Mississippi Choice ranked intermediate. Reel mowing at 2.2 cm plus grooming to a 1.9 cm depth reduced percent green cover on the majority of rating dates in 2006; however, this response was not observed in 2007. Reel mowing at 2.2 cm plus grooming to a 1.9 cm depth did not reduce thatch accumulation either year. Reductions in bulk density and increases in green cover, thatch accumulation, and saturated hydraulic conductivity were associated with overseeding, suggesting that this practice may protect bermudagrass athletic fields from both components of traffic stress: wear and soil compaction.
Molecular Analysis of GmFAD3A in Two Soybean Populations Segregating for the fan, fap1, and fapnc Loci
Authors: Cardinal Andrea J. , Burton Joseph W. , Camacho‐Roger Ana María , Whetten Rebecca , Chappell Andrew S. , Bilyeu Kristin D. , Auclair Jéròme , Dewey Ralph E.
Published: August 2011

Soybeans [Glycine max (L.) Merr.] have undesirable levels of polyunsaturated fatty acids in their oil that result in oxidative instability and poor flavor. The process of hydrogenation improves the stability but creates undesirable trans fats. Lines carrying fan genes have decreased linolenic acid (18:3) content. Changes in transcription or activity of the desaturase encoded by the GmFAD3 gene cause a reduction in 18:3 content in certain lines. The objectives of this study were to determine the molecular basis of the fan allele in PI 123440, develop molecular markers to assay for the GmFAD3 gene in lines carrying fan(PI 123440), and estimate the variation in the 18:3 explained by the GmFAD3A locus. Sequence analysis of the GmFAD3A from ‘Soyola’, the fan(PI 123440) allele, and ‘Dare’ showed no sequence polymorphisms that would alter the amino acid sequence of the enzyme. RNA blot analysis of a low‐18:3 line carrying a fan(PI 123440) allele, a line with normal 18:3 content, and three of their progenies showed a decrease in steady‐state FAD3A RNA levels in low‐18:3 lines. A marker for GmFAD3A was tested in two populations segregating for fan(PI 123440). Lines homozygous the GmFAD3A allele inherited from PI 123440 had a significant reduction in 18:3 when compared to lines homozygous for the GmFAD3A allele from the normal 18:3 parent. The differences between the two groups explained more than 77.5% of the genetic variation in 18:3 seed‐oil content in the populations. In summary, a reduction in the steady‐state mRNA levels of the GmFAD3A leads to a reduction in 18:3 synthesis within the developing seed in plants containing the fan(PI 123440) allele.
Genotype × Location Interaction Patterns and Testing Strategies for Oat in the Canadian Prairies
Authors: Yan Weikai , Fetch Jennifer Mitchell , Frégeau‐Reid Judith , Rossnagel Brian , Ames Nancy
Published: August 2011

The Canadian Prairies is one of the most important oat (Avena sativa L.) production regions in the world and oat breeding objectives for the region include high grain yield, groat content, and dietary fiber concentration. Using data from the 2004 through 2009 Western Cooperative Oat Registration trials, we investigated yearly genotype × location interaction patterns for grain yield, groat percentage, and dietary fiber concentration and the relationships among these traits. Despite large hectareage and wide geographical range, the Canadian Prairies was found to be relatively homogeneous and can be regarded as a single mega‐environment, with southern Manitoba tending to be slightly different from other portions of the region. Simulation indicated that three test locations could suffice to represent the region and provide reliable information for relative grain yield of differing genotypes. Groat percentage and dietary fiber content were more heritable than grain yield thus requiring fewer (no more than three) test locations for reliable selection. β‐glucan and total dietary fiber were closely correlated, thus the latter could potentially be improved via selecting for the former, which is simpler to determine, although more research is required in this area. However, dietary fiber content was negatively correlated with grain yield and/or groat content, constituting a challenge for breeding milling oats.
Selection and Adaptation to High Plant Density in the Iowa Stiff Stalk Synthetic Maize (Zea mays L.) Population
Authors: Brekke Brent , Edwards Jode , Knapp Allen
Published: August 2011

The plant density at which maize (Zea mays L.) hybrids achieve maximum grain yield has increased throughout the hybrid era, whereas grain yield on a per plant basis has increased little. Changes in grain yield, grain moisture, test weight, and stalk and root lodging have been well characterized in comparisons of commercial hybrids representing different eras of hybrid maize production but have yet to be examined in a recurrent selection program. The objective of this experiment was to determine if direct selection for grain yield and agronomic performance in the Iowa Stiff Stalk Synthetic (BSSS) population has indirectly improved adaptation to high plant density. Material from an unselected base population, BSSS, was compared to the most advanced cycles of selection from three different recurrent selection programs at seven Iowa locations in 2008 and 2009. Populations were compared at densities of 38,300, 57,400, 77,500, and 95,700 plants ha−1. Treatments were replicated twice at each location and arranged in a split plot design. Selection produced notable improvement in adaptation to high plant density for grain yield and stalk lodging. Selection did not have large impacts on density response for root lodging, test weight, or grain moisture. Because of the improvement in density response for grain yield and stalk lodging without major negative changes in other traits, our data suggest that selection has improved adaptation to high plant density in these populations.
Improving Emergence of Modified Phosphorus Composition Soybeans: Genotypes, Germplasm, Environments, and Selection
Authors: Maupin Laura M. , Rainey Katy M.
Published: August 2011

Commercial production of soybeans [Glycine max (L.) Merr.] with reduced phytate and increased inorganic phosphorus has nutritional benefits but is challenged by poor seedling emergence. An agronomic trial evaluated emergence of advanced lines derived from the CX1834 and V99‐5089 low phytate germplasm at six locations in 2009 and 2010. In 2010, seed produced in 12 environments was evaluated in an extended cold germination test (ECGT) and in a replicated field emergence test in Warsaw, VA. Objectives were to evaluate ECGT as a selection tool for improving germination and emergence of low phytate soybeans and to determine the effect of the seed production environment on emergence in different low phytate soybean germplasm. Genotypic, environmental, and the genotype × environment interaction effects were significant (p < 0.001) for emergence in the agronomic trial, ECGT, and field emergence test. Three lines were not significantly different from the two control cultivars for emergence in 12 environments. Yields of the best emerging lines were not significantly different from the control cultivars. The ECGT and field emergence test were significantly correlated (r = 0.78) but the ECGT severely reduced germination as compared with the field emergence test. Poor germination in the ECGT did not always translate to poor emergence under field conditions, preventing the use of ECGT as a selection tool or in determining seeding rates for the Southeast and Mid‐Atlantic regions.
A Rice Diversity Panel Evaluated for Genetic and Agro‐Morphological Diversity between Subpopulations and its Geographic Distribution
Authors: Liakat Ali M. , McClung Anna M. , Jia Melissa H. , Kimball Jennifer A. , McCouch Susan R. , Eizenga Georgia C.
Published: August 2011

A diverse collection of 409 Asian rice (Oryza sativa L.) accessions originating from 79 countries was fingerprinted with 36 simple sequence repeat (SSR) markers and evaluated for 18 agro‐morphological traits. Genetically, the accessions clustered into five ancestral groups (subpopulations), indica, aus, aromatic (Group V), tropical japonica, and temperate japonica, based on model‐based structure analysis. Thirty‐three accessions with less than 60% ancestry from any single group were identified as admixtures. Canonical discriminant analysis identified eight agro‐morphological traits (panicle number per plant, panicle length, plant height, flag leaf width, grain length, width, length:width ratio, and volume) as the main discriminatory characters among the rice accessions and between the subpopulations. Both SSR allele‐ and phenotypic trait‐based analyses indicated a close relationship between aus and indica and similarly between temperate japonica and tropical japonica. The aromatic (Group V) rice represents a distinct small group that is more closely related to tropical japonica based on SSR alleles but to aus and indica based on phenotype. A strong relationship between subpopulations and geographical distribution was observed. This rice diversity panel with the accompanying genetic and phenotypic information provides a valuable foundation for association mapping, understanding the basis of both genotypic and phenotypic differences within and between subpopulations, and rice improvement programs.
Variation in Biomass Yield, Cell Wall Components, and Agronomic Traits in a Broad Range of Diploid Alfalfa Accessions
Authors: Sakiroglu Muhammet , Moore Kenneth J. , Brummer E. Charles
Published: August 2011

Alfalfa (Medicago sativa L.), one of the most important forage legumes throughout the world, has potential as a biofuel crop. Breeding to improve biomass yield and stem composition will enhance the value of alfalfa. In this experiment, we evaluated 374 individual genotypes from 120 accessions of wild diploid alfalfa collected throughout the Northern Hemisphere and representing the three diploid subspecies, M. sativa subsp. falcata, M. sativa subsp. caerulea, and M. sativa subsp. hemicycla. We measured total biomass yield, stem cell wall constituents (neutral detergent fiber, acid detergent fiber, acid detergent lignin, glucose, xylose, and arabinose), and important agronomic traits in field trials at two Georgia locations in 2007 and 2008. A large amount of phenotypic variation exists in the diploid gene pool for all traits. Yield variation among accessions spanned more than an order of magnitude. High‐yielding accessions tended to have higher levels of cell wall constituents. Clustering of genotypes or accessions on the basis of phenotypic traits differed from the population structure pattern observed previously with molecular markers. The results show that phenotypic variation is very large in diploids, offering a potentially useful pool of alleles for future breeding efforts.