bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancing Mitochondrial Calcium Buffering Capacity Reduces Aggregation of Misfolded SOD1 and Motor Neuron Cell Death without Extending Survival in Mouse Models of Inherited Amyotrophic Lateral Sclerosis
Authors: Parone Philippe A. , Da Cruz Sandrine , Han Joo Seok , McAlonis-Downes Melissa , Vetto Anne P. , Lee Sandra K. , Tseng Eva , Cleveland Don W.
Published: March 2013

Mitochondria have been proposed as targets for toxicity in amyotrophic lateral sclerosis (ALS), a progressive, fatal adult-onset neurodegenerative disorder characterized by the selective loss of motor neurons. A decrease in the capacity of spinal cord mitochondria to buffer calcium (Ca2+) has been observed in mice expressing ALS-linked mutants of SOD1 that develop motor neuron disease with many of the key pathological hallmarks seen in ALS patients. In mice expressing three different ALS-causing SOD1 mutants, we now test the contribution of the loss of mitochondrial Ca2+-buffering capacity to disease mechanism(s) by eliminating ubiquitous expression of cyclophilin D, a critical regulator of Ca2+-mediated opening of the mitochondrial permeability transition pore that determines mitochondrial Ca2+content. A chronic increase in mitochondrial buffering of Ca2+in the absence of cyclophilin D was maintained throughout disease course and was associated with improved mitochondrial ATP synthesis, reduced mitochondrial swelling, and retention of normal morphology. This was accompanied by an attenuation of glial activation, reduction in levels of misfolded SOD1 aggregates in the spinal cord, and a significant suppression of motor neuron death throughout disease. Despite this, muscle denervation, motor axon degeneration, and disease progression and survival were unaffected, thereby eliminating mutant SOD1-mediated loss of mitochondrial Ca2+buffering capacity, altered mitochondrial morphology, motor neuron death, and misfolded SOD1 aggregates, as primary contributors to disease mechanism for fatal paralysis in these models of familial ALS.
Ultra-High 7T MRI of Structural Age-Related Changes of the Subthalamic Nucleus
Authors: Keuken Max C. , Bazin Pierre-Louis , Schäfer Andreas , Neumann Jane , Turner Robert , Forstmann Birte U.
Published: March 2013

The subthalamic nucleus (STh) is a small subcortical structure which is involved in regulating motor as well as cognitive functions. Due to its small size and close proximity to other small subcortical structures, it has been a challenge to localize and visualize it using magnetic resonance imaging (MRI). Currently there are several standard atlases available that are used to localize the STh in functional MRI studies and clinical procedures such as deep brain stimulation (DBS). DBS is an increasingly common neurosurgical procedure that has been successfully used to alleviate motor symptoms present in Parkinson's disease. However, current atlases are based on low sample sizes and restricted age ranges (Schaltenbrand and Wahren, 1977), and hence the use of these atlases effectively ignores the substantial structural brain changes that are associated with aging. In the present study, ultra-high field 7 tesla (T) magnetic resonance imaging (MRI) in humans was used to visualize and segment the STh in young, middle-aged, and elderly participants. The resulting probabilistic atlas maps for all age groups show that the STh shifts in the lateral direction with increasing age. In sum, the results of the present study suggest that age has to be taken into account in atlases for the optimal localization of the STh in healthy and diseased brains.
Selective Effects of Dopamine Depletion and L-DOPA Therapy on Learning-Related Firing Dynamics of Striatal Neurons
Authors: Hernandez Ledia F. , Kubota Yasuo , Hu Dan , Howe Mark W. , Lemaire Nuné , Graybiel Ann M.
Published: March 2013

Despite evidence that dopamine neurotransmission in the striatum is critical for learning as well as for movement control, little is yet known about how the learning-related dynamics of striatal activity are affected by dopamine depletion, a condition faced in Parkinson's disease. We made localized intrastriatal 6-hydroxydopamine lesions in rats and recorded within the dopamine-depleted sensorimotor striatal zone and its contralateral correspondent as the animals learned a conditional maze task. Rather than producing global, nonspecific elevations in firing rate across the task, the dopamine depletion altered striatal projection neuron activity and fast-spiking interneuron activity selectively, with sharply task-specific and cell type-specific effects, and often, with learning-stage selective effects as well. Striatal projection neurons with strong responses during the maze runs had especially elevated responsiveness during the maze runs. Projection neurons that, instead, fired most strongly before maze running showed elevated pre-start firing rates, but not during maze running, as learning progressed. The intrastriatal dopamine depletion severely affected the learning-related patterning of fast-spiking interneuron ensembles, especially during maze running and after extended training. Remarkably, L-DOPA treatment almost entirely reversed the depletion-induced elevations in pre-run firing of the projection neurons, and elevated their responses around start and end of maze runs. By contrast, L-DOPA failed to normalize fast-spiking interneuron activity. Thus the effects of striatal dopamine depletion and restoration on striatal activity are highly dependent not only on cell type, as previously shown, but also on the behavioral activity called for and the state of behavioral learning achieved.
Multiphasic Temporal Dynamics in Responses of Midbrain Dopamine Neurons to Appetitive and Aversive Stimuli
Authors: Fiorillo Christopher D. , Song Minryung R. , Yun Sora R.
Published: March 2013

The transient response of dopamine neurons has been described as reward prediction error (RPE), with activation or suppression by events that are better or worse than expected, respectively. However, at least a minority of neurons are activated by aversive or high-intensity stimuli, casting doubt on the generality of RPE in describing the dopamine signal. To overcome limitations of previous studies, we studied neuronal responses to a wider variety of high-intensity and aversive stimuli, and we quantified and controlled aversiveness through a choice task in which macaques sacrificed juice to avoid aversive stimuli. Whereas most previous work has portrayed the RPE as a single impulse or “phase,” here we demonstrate its multiphasic temporal dynamics. Aversive or high-intensity stimuli evoked a triphasic sequence of activation-suppression-activation extending over a period of 40–700 ms. The initial activation at short latencies (40–120 ms) reflected sensory intensity. The influence of motivational value became dominant between 150 and 250 ms, with activation in the case of appetitive stimuli, and suppression in the case of aversive and neutral stimuli. The previously unreported late activation appeared to be a modest “rebound” after strong suppression. Similarly, strong activation by reward was often followed by suppression. We suggest that these “rebounds” may result from overcompensation by homeostatic mechanisms in some cells. Our results are consistent with a realistic RPE, which evolves over time through a dynamic balance of excitation and inhibition.
Diversity and Homogeneity in Responses of Midbrain Dopamine Neurons
Authors: Fiorillo Christopher D. , Yun Sora R. , Song Minryung R.
Published: March 2013

Dopamine neurons of the ventral midbrain have been found to signal a reward prediction error that can mediate positive reinforcement. Despite the demonstration of modest diversity at the cellular and molecular levels, there has been little analysis of response diversity in behaving animals. Here we examine response diversity in rhesus macaques to appetitive, aversive, and neutral stimuli having relative motivational values that were measured and controlled through a choice task. First, consistent with previous studies, we observed a continuum of response variability and an apparent absence of distinct clusters in scatter plots, suggesting a lack of statistically discrete subpopulations of neurons. Second, we found that a group of “sensitive” neurons tend to be more strongly suppressed by a variety of stimuli and to be more strongly activated by juice. Third, neurons in the “ventral tier” of substantia nigra were found to have greater suppression, and a subset of these had higher baseline firing rates and late “rebound” activation after suppression. These neurons could belong to a previously identified subgroup of dopamine neurons that express high levels of H-type cation channels but lack calbindin. Fourth, neurons further rostral exhibited greater suppression. Fifth, although we observed weak activation of some neurons by aversive stimuli, this was not associated with their aversiveness. In conclusion, we find a diversity of response properties, distributed along a continuum, within what may be a single functional population of neurons signaling reward prediction error.
Oligodendroglial Expression of TrkB Independently Regulates Myelination and Progenitor Cell Proliferation
Authors: Wong Agnes W. , Xiao Junhua , Kemper Dennis , Kilpatrick Trevor J. , Murray Simon S.
Published: March 2013

The neurotrophin brain-derived neurotrophic factor (BDNF) has been implicated in regulating CNS myelination. BDNF mutant mice exhibit a hypomyelinating phenotype, and BDNF exerts distinct effects upon oligodendroglial proliferation, differentiation, and myelinationin vitro. To investigate the precise influence that BDNF exerts in regulating CNS myelinationin vivo, we have generated conditional knock-out mice in which TrkB has been deleted specifically in oligodendrocytes. Deletion of TrkB disrupted normal oligodendrocyte myelination, resulting in a significant reduction in myelin protein expression and myelination of CNS white matter tracts during development. Importantly, conditional knock-out mice exhibited normal numbers of mature oligodendrocytes and normal numbers of myelinated axons; however, myelin thickness was significantly reduced during development. These data indicate that while TrkB expression in oligodendrocytes plays no role in the initial contact with axons, it exerts an important influence in subsequent stages to promote myelin ensheathment. The conditional knock-out mice also exhibited an increased density of oligodendrocyte progenitor cells (OPCs) in CNS white matter tracts. Concordant with these results,in vitroanalyses using OPCs subjected to TrkB knockdown also revealed increased OPC proliferation. Our data suggested this effect was dependent upon TrkC and p75 expression. Thus, our data demonstrate that TrkB expression in oligodendroglia exerts a direct effect on oligodendrocytes to promote myelination and an indirect effect upon the OPC population, modifying their proliferative potential.
Presynaptic Calcium Influx Controls Neurotransmitter Release in Part by Regulating the Effective Size of the Readily Releasable Pool
Authors: Thanawala Monica S. , Regehr Wade G.
Published: March 2013

The steep calcium dependence of synaptic strength that has been observed at many synapses is thought to reflect a calcium dependence of the probability of vesicular exocytosis (p), with the cooperativity of three to six corresponding to the multiple calcium ion binding sites on the calcium sensor responsible for exocytosis. Here we test the hypothesis that the calcium dependence of the effective size of the readily releasable pool (RRP) also contributes to the calcium dependence of release at the calyx of Held synapse in mice. Using two established methods of quantifying neurotransmitter release evoked by action potentials (effective RRP), we find that when calcium influx is changed by altering the external calcium concentration, the calcium cooperativity ofpis insufficient to account for the full calcium dependence of EPSC size; the calcium dependence of the RRP size also contributes. Reducing calcium influx by blocking R-type voltage-gated calcium channels (VGCCs) with Ni2+, or by blocking P/Q-type VGCCs with ω-agatoxin IVA also changes EPSC amplitude by reducing bothpand the effective RRP size. This suggests that the effective RRP size is dependent on calcium influx through VGCCs. Furthermore, activation of GABABreceptors, which reduces presynaptic calcium through VGCCs without other significant effects on release, also reduces the effective RRP size in addition to reducingp. These findings indicate that calcium influx regulates the RRP size along withp, which contributes to the calcium dependence of synaptic strength, and it influences the manner in which presynaptic modulation of presynaptic calcium channels affects neurotransmitter release.
Presynaptic Serotonergic Gating of the Subthalamonigral Glutamatergic Projection
Authors: Ding Shengyuan , Li Li , Zhou Fu-Ming
Published: March 2013

The GABAergic projection neurons in the substantia nigra pars reticulata (SNr) are key basal ganglia output neurons. The activity of these neurons is critically influenced by the glutamatergic projection from the subthalamic nucleus (STN). The SNr also receives an intense serotonin (5-HT) innervation, raising the possibility that 5-HT may regulate the STN→SNr glutamatergic transmission and the consequent STN-triggered spike firing in SNr neurons. Here we show that 5-HT reduced STN stimulation-evoked long-lasting polysynaptic complex EPSCs in SNr GABA neurons. This inhibitory 5-HT effect was mimicked by the 5-HT1B receptor agonist CP93129 and blocked by the 5-HT1B antagonist NAS-181. 5-HT1A receptor ligands were ineffective. Additionally, 5-HT and CP93129 reduced the frequency but not the amplitude of miniature EPSCs, suggesting a reduced vesicular release. 5-HT and CP93129 also decreased the amplitude but increased the paired pulse ratio of the monosynaptic EPSCs in SNr GABA neurons, indicating a presynaptic 5-HT1B receptor-mediated inhibition of glutamate release. Furthermore, 5-HT and CP93129 inhibited STN-triggered burst firing in SNr GABA neurons, and CP93129's inhibitory effect was strongest when puffed to STN→SNr axon terminals in SNr, indicating a primary role of the 5-HT1B receptors in these axon terminals. Finally, the 5-HT1B receptor antagonist NAS-181 increased the STN-triggered complex EPSCs and burst firing in SNr GABA neurons, demonstrating the effects of endogenous 5-HT. These results suggest that nigral 5-HT, via presynaptic 5-HT1B receptor activation, gates the excitatory STN→SNr projection, reduces burst firing in SNr GABA neurons, and thus may play a critical role in movement control.
Intensive Reasoning Training Alters Patterns of Brain Connectivity at Rest
Authors: Mackey Allyson P. , Miller Singley Alison T. , Bunge Silvia A.
Published: March 2013

Patterns of correlated activity among brain regions reflect functionally relevant networks that are widely assumed to be stable over time. We hypothesized that if these correlations reflect the prior history of coactivation of brain regions, then a marked shift in cognition could alter the strength of coupling between these regions. We sought to test whether intensive reasoning training in humans would result in tighter coupling among regions in the lateral frontoparietal network, as measured with resting-state fMRI (rs-fMRI). Rather than designing an artificial training program, we studied individuals who were preparing for a standardized test that places heavy demands on relational reasoning, the Law School Admissions Test (LSAT). LSAT questions require test takers to group or sequence items according to a set of complex rules. We recruited young adults who were enrolled in an LSAT course that offers 70 h of reasoning instruction (n= 25), and age- and IQ-matched controls intending to take the LSAT in the future (n= 24). rs-fMRI data were collected for all subjects during two scanning sessions separated by 90 d. An analysis of pairwise correlations between brain regions implicated in reasoning showed that fronto-parietal connections were strengthened, along with parietal-striatal connections. These findings provide strong evidence for neural plasticity at the level of large-scale networks supporting high-level cognition.
Sumoylated MEF2A Coordinately Eliminates Orphan Presynaptic Sites and Promotes Maturation of Presynaptic Boutons
Authors: Yamada Tomoko , Yang Yue , Huang Ju , Coppola Giovanni , Geschwind Daniel H. , Bonni Azad
Published: March 2013

Presynaptic differentiation of axons plays a fundamental role in the establishment of neuronal connectivity. However, the mechanisms that govern presynaptic differentiation in the brain remain largely to be elucidated. We report that knockdown of the transcription factor MEF2A in primary neurons and importantly in the rat cerebellar cortexin vivorobustly increases the density of orphan presynaptic sites. Remarkably, the sumoylated transcriptional repressor form of MEF2A drives the suppression of orphan presynaptic sites. We also identify the gene encoding synaptotagmin 1 (Syt1), which acts locally at presynaptic sites, as a direct repressed target gene of sumoylated MEF2A in neurons, and demonstrate that repression of Syt1 mediates MEF2A-dependent elimination of orphan presynaptic sites. Finally, we uncover a role for the MEF2A-induced elimination of orphan presynaptic sites in the accumulation of presynaptic material at large maturing presynaptic boutons. Collectively, these findings define sumoylated MEF2A and Syt1 as components of a novel cell-intrinsic mechanism that orchestrates presynaptic differentiation in the mammalian brain. Our study has important implications for understanding neuronal connectivity in brain development and disease.
Sustained Interleukin-1β Overexpression Exacerbates Tau Pathology Despite Reduced Amyloid Burden in an Alzheimer's Mouse Model
Authors: Ghosh Simantini , Wu Michael D. , Shaftel Solomon S. , Kyrkanides Stephanos , LaFerla Frank M. , Olschowka John A. , O'Banion M. Kerry
Published: March 2013

Neuroinflammation is an important component of Alzheimer's disease (AD) pathogenesis and has been implicated in neurodegeneration. Interleukin-1 (IL-1), a potent inflammatory cytokine in the CNS, is chronically upregulated in human AD and believed to serve as part of a vicious inflammatory cycle that drives AD pathology. To further understand the role of IL-1β in AD pathogenesis, we used an inducible model of sustained IL-1β overexpression (IL-1βXAT) developed in our laboratory. The triple transgenic mouse model of AD, which develops plaques and tangles later in its life cycle, was bred with IL-1βXATmice, and effects of IL-1β overexpression on AD pathology were assessed in F1 progeny. After 1 and 3 months of transgene expression, we found robust increases in tau phosphorylation despite an ∼70–80% reduction in amyloid load and fourfold to sixfold increase in plaque-associated microglia, as well as evidence of greater microglial activation at the site of inflammation. We also found evidence of increased p38 mitogen-activated protein kinase and glycogen synthase kinase-3β activity, which are believed to contribute to tau phosphorylation. Thus, neuroinflammation regulates amyloid and tau pathology in opposing ways, suggesting that it provides a link between amyloid accumulation and changes in tau and raising concerns about the use of immunomodulatory therapies in AD.
Immunogenicity, Efficacy, Safety, and Mechanism of Action of Epitope Vaccine (Lu AF20513) for Alzheimer's Disease: Prelude to a Clinical Trial
Authors: Davtyan Hayk , Ghochikyan Anahit , Petrushina Irina , Hovakimyan Armine , Davtyan Arpine , Poghosyan Anna , Marleau Annette M. , Movsesyan Nina , Kiyatkin Anatoly , Rasool Suhail , Larsen Anna Kirstine , Madsen Peter Juul , Wegener Karen Malene , Ditlevsen Dorte Kornerup , Cribbs David H. , Pedersen Lars Ostergaard , Agadjanyan Michael G.
Published: March 2013

The Alzheimer's disease (AD) process is understood to involve the accumulation of amyloid plaques and tau tangles in the brain. However, attempts at targeting the main culprits, neurotoxic Aβ peptides, have thus far proven unsuccessful for improving cognitive function. Recent clinical trials with passively administrated anti-Aβ antibodies failed to slow cognitive decline in mild to moderate AD patients, but suggest that an immunotherapeutic approach could be effective in patients with mild AD. Using an AD mouse model (Tg2576), we tested the immunogenicity (cellular and humoral immune responses) and efficacy (AD-like pathology) of clinical grade Lu AF20513 vaccine. We found that Lu AF20513 induces robust “non-self” T-cell responses and the production of anti-Aβ antibodies that reduce AD-like pathology in the brains of Tg2576 mice without inducing microglial activation and enhancing astrocytosis or cerebral amyloid angiopathy. A single immunization with Lu AF20513 induced strong humoral immunity in mice with preexisting memory T-helper cells. In addition, Lu AF20513 induced strong humoral responses in guinea pigs and monkeys. These data support the translation of Lu AF20513 to the clinical setting with the aims of: (1) inducing therapeutically potent anti-Aβ antibody responses in patients with mild AD, particularly if they have memory T-helper cells generated after immunizations with conventional tetanus toxoid vaccine, and (2) preventing pathological autoreactive T-cell responses.
Encoding by Synchronization in the Primate Striatum
Authors: Adler Avital , Finkes Inna , Katabi Shiran , Prut Yifat , Bergman Hagai
Published: March 2013

Information is encoded in the nervous system through the discharge and synchronization of single neurons. The striatum, the input stage of the basal ganglia, is divided into three territories: the putamen, the caudate, and the ventral striatum, all of which converge onto the same motor pathway. This parallel organization suggests that there are multiple and competing systems in the basal ganglia network controlling behavior. To explore which mechanism(s) enables the different striatal domains to encode behavioral events and to control behavior, we compared the neural activity of phasically active neurons [medium spiny neurons (MSNs), presumed projection neurons] and tonically active neurons (presumed cholinergic interneurons) across striatal territories from monkeys during the performance of a well practiced task. Although neurons in all striatal territories displayed similar spontaneous discharge properties and similar temporal modulations of their discharge rates to the behavioral events, their correlation structure was profoundly different. The distributions of signal and noise correlation of pairs of putamen MSNs were strongly shifted toward positive correlations and these two measures were correlated. In contrast, MSN pairs in the caudate and ventral striatum displayed symmetrical, near-zero signal and noise correlation distributions. Furthermore, only putamen MSN pairs displayed different noise correlation dynamics to rewarding versus neutral/aversive cues. Similarly, the noise correlation between tonically active neuron pairs was stronger in the putamen than in the caudate. We suggest that the level of synchronization of the neuronal activity and its temporal dynamics differentiate the striatal territories and may thus account for the different roles that striatal domains play in behavioral control.
GDNF and Endothelin 3 Regulate Migration of Enteric Neural Crest-Derived Cells via Protein Kinase A and Rac1
Authors: Goto Akihiro , Sumiyama Kenta , Kamioka Yuji , Nakasyo Eiji , Ito Keisuke , Iwasaki Mitsuhiro , Enomoto Hideki , Matsuda Michiyuki
Published: March 2013

Enteric neural crest-derived cells (ENCCs) migrate from the anterior foregut in a rostrocaudal direction to colonize the entire gastrointestinal tract and to form the enteric nervous system. Genetic approaches have identified many signaling molecules regulating the migration of ENCCs; however, it remains elusive how the activities of the signaling molecules are regulated spatiotemporally during migration. In this study, transgenic mice expressing biosensors based on Förster resonance energy transfer were generated to video the activity changes of the signaling molecules in migrating ENCCs. In an organ culture of embryonic day 11.25 (E11.25) to E13 guts, ENCCs at the rostral wavefront migrated as a cellular chain faster than the following ENCCs that formed a network. The faster-migrating cells at the wavefront exhibited lower protein kinase A (PKA) activity than did the slower-migrating trailing cells. The activities of Rac1 and Cdc42 exhibited an inverse correlation with the PKA activity, and PKA activation decreased the Rac1 activity and migration velocity. PKA activity in ENCCs was correlated positively with the distribution of GDNF and inversely with the distribution of endothelin 3 (ET-3). Accordingly, PKA was activated by GDNF and inhibited by ET-3 in cultured ENCCs. Finally, although the JNK and ERK pathways were previously reported to control the migration of ENCCs, we did not find any correlation of JNK or ERK activity with the migration velocities. These results suggest that external cues regulate the migration of ENCCs by controlling PKA activity, but not ERK or JNK activity, and argue for the importance of live imaging of signaling molecule activities in developing organs.
Layer-Specific Interference with Cholinergic Signaling in the Prefrontal Cortex by Smoking Concentrations of Nicotine
Authors: Poorthuis Rogier B. , Bloem Bernard , Verhoog Matthijs B. , Mansvelder Huibert D.
Published: March 2013

Adolescence is a period in which the developing prefrontal cortex (PFC) is sensitive to maladaptive changes when exposed to nicotine. Nicotine affects PFC function and repeated exposure to nicotine during adolescence impairs attention performance and impulse control during adulthood. Nicotine concentrations experienced by smokers are known to desensitize nicotinic acetylcholine receptors (nAChRs), but the impact thereof on PFC circuits is poorly understood. Here, we investigated how smoking concentrations of nicotine (100–300 nm) interfere with cholinergic signaling in the mouse PFC. nAChR desensitization depends on subunit composition. Since nAChR subunits are differentially expressed across layers of the PFC neuronal network, we hypothesized that cholinergic signaling through nAChRs across layers would suffer differentially from exposure to nicotine. Throughout the PFC, nicotine strongly desensitized responses to ACh in neurons expressing β2* nAChRs, whereas ACh responses mediated by α7 nAChRs were not hampered. The amount of desensitization of β2* nAChR currents depended on neuron type and cortical layer. β2*-mediated responses of interneurons in LII–III and LVI completely desensitized, while cholinergic responses in LV interneurons and LVI pyramidal cells showed less desensitization. This discrepancy depended on α5 subunit expression. Two-photon imaging of neuronal population activity showed that prolonged exposure to nicotine limited cholinergic signaling through β2* nAChRs to deep PFC layers where α5 subunits were expressed. Together, our results demonstrate a layer-dependent decrease in cholinergic activation of the PFC through nAChRs by nicotine. These mechanisms may be one of the first steps leading up to the pathophysiological changes associated with nicotine exposure during adolescence.
Blockade of Stimulus Convergence in Amygdala Neurons Disrupts Taste Associative Learning
Authors: Hashikawa Koichi , Naka Masamitsu , Nakayama Daisuke , Matsumoto Nobuyoshi , Neve Rachael , Matsuki Norio
Published: March 2013

Humans and non-human animals learn associations of temporally contingent stimuli to better cope with the changing environment. In animal models of classical conditioning, a neutral conditioned stimulus (CS) predicts an aversive unconditioned stimulus (US). Several lines of indirect evidence indicate that this learning may rely on stimulus convergence in a subset of neurons, but this hypothesis has not been directly tested. In the current study, we tested this hypothesis using a pharmacogenetic approach, the cAMP response element-binding protein (CREB)/Allatostatin Receptor system, to target a subset of amygdala neurons receiving convergent stimuli in mice during conditioned taste aversion. Virally infected basolateral amygdala neurons with higher CREB levels were predominantly active during CS presentation. Blocking stimulus convergence in infected neurons by silencing them during US disrupted taste associative memory. Moreover, silencing infected neurons only during CS also disrupted associative memory formation. These results provide support for the notion that convergent inputs of CS and US in a subpopulation of neurons are critical for associative memory formation.
Rapid, Activity-Independent Turnover of Vesicular Transmitter Content at a Mixed Glycine/GABA Synapse
Authors: Apostolides Pierre F. , Trussell Laurence O.
Published: March 2013

The release of neurotransmitter via the fusion of transmitter-filled, presynaptic vesicles is the primary means by which neurons relay information. However, little is known regarding the molecular mechanisms that supply neurotransmitter destined for vesicle filling, the endogenous transmitter concentrations inside presynaptic nerve terminals, or the dynamics of vesicle refilling after exocytosis. We addressed these issues by recording from synaptically coupled pairs of glycine/GABA coreleasing interneurons (cartwheel cells) of the mouse dorsal cochlear nucleus. We find that the plasma membrane transporter GlyT2 and the intracellular enzyme glutamate decarboxylase supply the majority of glycine and GABA, respectively. Pharmacological block of GlyT2 or glutamate decarboxylase led to rapid and complete rundown of transmission, whereas increasing GABA synthesis via intracellular glutamate uncaging dramatically potentiated GABA release within 1 min. These effects were surprisingly independent of exocytosis, indicating that prefilled vesicles re-equilibrated upon acute changes in cytosolic transmitter. Titration of cytosolic transmitter with postsynaptic responses indicated that endogenous, nonvesicular glycine/GABA levels in nerve terminals are 5–7 mm, and that vesicular transport mechanisms are not saturated under basal conditions. Thus, cytosolic transmitter levels dynamically set the strength of inhibitory synapses in a release-independent manner.
Views of Academic and Community Partners Regarding Participant Protections and Research Integrity: A Pilot Focus Group Study
Authors: Anderson Emily E.
Published: March 2013

When community partners have direct interaction with human research participants, it is important to consider potential threats to participant protections and research integrity. Few studies have directly compared the views of academic and community partners. This pilot focus group study explores the views of academic partners (APs) and community partners (CPs) regarding challenges to the protection of research participants and research integrity in community-engaged research (CEnR). Data are analyzed to understand how APs and CPs define and think about ethical problems and how meaning and analysis may differ between the two groups. Findings have implications for the development of research ethics training materials for academic-community research partnerships and IRBs; Revised best practices for CEnR; Revised and future research on ethical issues in CEnR.
African American Children's Perceptions of HIV-Focused Community-Based Participatory Research
Authors: Traube Dorian E. , Kerkorian Dara , Cederbaum Julie A. , Bhupali Chetan , McKay Mary M.
Published: March 2013

We examined factors influencing informed assent, initial involvement, and ongoing involvement in HIV-focused CBPR research for African American children. Study participants (n = 170) were recruited from the Collaborative HIV and Adolescent Mental Health Project and completed an interview format designed to assess attitudes about research activities. Data were analyzed using a mixed-methods approach. Three themes emerged via quantitative and qualitative data analysis: (1) motivation for the child to participate in the research; Revised (2) trust in researchers; Revised and (3) understanding of the informed assent process. Findings from this study can help researchers develop procedures facilitating ethics boards to assess the appropriateness of child assent in HIV-focused community-based participatory research.
Vitamin D dose response is underestimated by Endocrine Society's Clinical Practice Guideline
Authors: McKenna Malachi J , Murray Barbara F
Published: March 2013

Objective

The recommended daily intakes of vitamin D according to the recent Clinical Practice Guideline (CPG) of the Endocrine Society are three- to fivefold higher than the Institute of Medicine (IOM) report. We speculated that these differences could be explained by different mathematical approaches to the vitamin D dose response.

Methods

Studies were selected if the daily dose was ≤2000 IU/day, the duration exceeded 3 months, and 25-hydroxyvitamin D (25OHD) concentrations were measured at baseline and post-therapy. The rate constant was estimated according to the CPG approach. The achieved 25OHD result was estimated according to the following: i) the regression equation approach of the IOM; ii) the regression approach of the Vitamin D Supplementation in Older Subjects (ViDOS) study; and iii) the CPG approach using a rate constant of 2.5 (CPG2.5) and a rate constant of 5.0 (CPG5.0). The difference between the expected and the observed 25OHD result was expressed as a percentage of observed and analyzed for significance against a value of 0% for the four groups.

Results

Forty-one studies were analyzed. The mean (95% CI) rate constant was 5.3 (4.4–6.2) nmol/l per 100 IU per day, on average twofold higher than the CPG rate constant. The mean (95% CI) for the difference between the expected and observed expressed as a percentage of observed was as follows: i) IOM, −7 (−16,+2)% (t=1.64, P=0.110); ii) ViDOS, +2 (−8,+12)% (t=0.40, P=0.69); iii) CPG2.5, −21 (−27,−15)% (t=7.2, P<0.0001); and iv) CPG5.0+3 (−4,+10)% (t=0.91, P=0.366).

Conclusion

The CPG ‘rule of thumb’ should be doubled to 5.0 nmol/l (2.0 ng/ml) per 100 IU per day, adopting a more risk-averse position.
Neuropsychological dysfunction in idiopathic hypoparathyroidism and its relationship with intracranial calcification and serum total calcium
Authors: Aggarwal Sameer , Kailash Suparna , Sagar Rajesh , Tripathi Manjari , Sreenivas Vishnubhatla , Sharma Raju , Gupta Nandita , Goswami Ravinder
Published: March 2013

Background

There is limited information on neuropsychological and neurological dysfunctions in patients with idiopathic hypoparathyroidism (IH).

Objective

To assess neuropsychological and neurological dysfunctions in IH and its associated factors in a cross-sectional design.

Method

Neuropsychological functions were assessed in 62 patients with IH and 70 controls using a battery of cognitive tests. Neurological assessment included extrapyramidal and cerebellar signs. Assessment of intracranial calcification and volume of basal ganglia calcification (BGC) were made on computed tomography and of calcium control by averaging serum total calcium values available during the follow-up.

Results

A significantly higher proportion of patients with IH showed neuropsychological dysfunctions than controls (32.3 (95% CI: 20.9–45.3) vs 5.7% (95% CI: 1.6–14.0),P<0.001). Neurological signs were present in 35.5% patients (extrapyramidal: 16.1%; cerebellar: 20.9%). Volume of BGC and number of sites with intracranial calcifications including cerebellum/dentate were comparable in patients with and without neuropsychological, extrapyramidal or cerebellar dysfunctions. Cognitive dysfunction score was lower by 1.7 points in males than in females (P=0.02) and increased by 0.21 and 5.5 for each year increase in the duration of illness (P=0.001) and one unit increase in serum calcium–phosphorus product (P=0.01) respectively. The scores improved by 0.27 for every mg% increase in serum calcium (P=0.001).

Conclusion

Neuropsychological dysfunctions are present in up to one-third of patients with IH and correlate with duration of illness, female gender, serum calcium and calcium–phosphorus product during follow-up but not with intracranial calcification. These dysfunctions may affect their daily functions, safety and drug compliance.
Autonomic nervous system balance in children and adolescents with craniopharyngioma and hypothalamic obesity
Authors: Cohen Michal , Syme Catriona , McCrindle Brian W , Hamilton Jill
Published: March 2013

Objective

Dysregulation of the autonomic nervous system is thought to be involved in craniopharyngioma-related hypothalamic obesity (CRHO). Increased parasympathetic activity and decreased sympathetic activity have been suggested. We aimed to study autonomic activity using heart rate variability (HRV) and biochemical measures in youth with CRHO compared with controls and to explore relationships between obesity and autonomic indices.

Design

A cross-sectional study of 16 youth with CRHO and 16 controls matched for sex, age, and BMI.

Methods

Anthropometrics, fasting blood-work, resting energy expenditure (REE), 24-h HRV, and 24-h urine catecholamines were assessed. Quality of life, sleepiness, and autonomic symptoms were evaluated. Power spectral analysis of the HRV was performed.

Results

HRV power spectral analysis parameters of both parasympathetic activity (mean high frequency (HF (ms2)) 611±504 vs 459±336,P=0.325) and sympathetic activity (median low frequency/HF 1.62 (1.37, 2.41) vs 1.89 (1.44, 2.99),P=0.650) did not differ between the groups. Parasympathetic activity negatively correlated with central adiposity in both groups (r=−0.53,P=0.034 andr=−0.54,P=0.029) and sympathetic activity positively correlated with central adiposity in CRHO (r=0.51,P=0.043). Youth with CRHO had significantly lower REE; lower health and activity scores in the quality of life questionnaires, and higher sleepiness scores.

Conclusions

Autonomic activity was similar in CRHO and control subjects. The degree of central adiposity correlated negatively with parasympathetic activity and positively with sympathetic activity in children with CRHO. These results provide a new perspective regarding autonomic balance in this unique patient population.
Electronic effects in Emission of core/shell CdSe/ZnS Quantum dots conjugated to anti-Interleukin 10 antibodies
Authors: Douda Janna , Lopez de la Luz Oscar S. , Díaz Cano Aaron I.
Published: March 2013

Papers in the Appendix were published in electronic format as Volume 1534
Biomimetic method for metallic nanostructured mesoscopic models fabrication
Authors: Strukov Gennady V. , Strukova Galina K.
Published: March 2013

Various metallic structures of complex shape, resembling natural objects such as plants, mushrooms, and seashells, were produced when growing nanowires by means of pulsed current electroplating in porous membranes. These structures occur as the result of nanowires self-assembling (biomimetics) if the electroplating is continued after the nanowires reach the membrane surface. By varying the membrane geometry and the pulsed current parameters, and alternating electroplating from two baths with different electrolytes, various models were fabricated, including a hollow container with wall thickness of 10-30 nm. The possibility of shape regulation for models was demonstrated: in certain conditions, mushroom- and shell-like convex-concave models of the same kind were obtained. The hierarchical structure of models at the nano-, micro- and mesoscopic levels is shown through fragmentation and chemical etching. This biomimetic method suggests an analogy between the shape-forming processes of natural plants and their metallic models. Nanostructured mesoscopic objects of metals (Ag, Pd, Rh, Ni, Bi), alloys (PdNi, PdCo, PbIn) as well as their combinations (PdNi/ Pb, PdNi/ PbIn) were obtained. The technological simplicity of the present method makes it suitable for fabricating nanostructured materials that may be efficient in catalysis, superhydrophobic applications, medical filters, and nanoplasmonics.
Resistance to Glyphosate in Palmer Amaranth (Amaranthus palmeri) Populations from New Mexico Pecan Orchards
Authors: Mohseni-Moghadam Mohsen , Schroeder Jill , Heerema Richard , Ashigh Jamshid
Published: March 2013

Two populations of Palmer amaranth suspected of being resistant to glyphosate have been reported since 2007 in pecan orchards in Doña Ana County, New Mexico. The objectives of the study were to confirm and evaluate the level of resistance, to evaluate the effectiveness of alternative herbicide mechanisms of action, and to compare the cost of effective alternative herbicides for weed management in pecan orchards. Greenhouse experiments indicated that the resistant populations were able to survive glyphosate at 736 g ae ha−1. Compared with a susceptible (S) population, one of the resistant (R) populations had sevenfold resistance to glyphosate. POST application of 12 herbicides, with five different mechanisms of action, all provided at least 88% control of both R and S populations when applied at their recommended field rates. PRE application of trifluralin and metolachlor also provided more than 99% control of R and S populations. The results of field studies indicated that the financial benefit of season-long weed management with glyphosate, in pecan orchards, was comparable with some of the tested alternative herbicides.
Influence of Palmer Amaranth (Amaranthus palmeri) on the Critical Period for Weed Control in Plasticulture-Grown Tomato
Authors: Garvey Paul V. , Meyers Stephen L. , Monks David W. , Coble Harold D.
Published: March 2013

Field studies were conducted in 1996, 1997, and 1998 at Clinton, NC, to determine the influence of Palmer amaranth establishment and removal periods on the yield and quality of plasticulture-grown ‘Mountain Spring' fresh market tomato. Treatments consisted of 14 Palmer amaranth establishment and removal periods. Half of the treatments were weed removal treatments (REM), in which Palmer amaranth was sowed at the time tomato transplanting and allowed to remain in the field for 0 (weed-free all season), 2, 3, 4, 6, 8, or 10 wk after transplanting (WAT). The second set of the treatments, weed establishment treatments (EST), consisted of sowing Palmer amaranth 0 (weedy all season), 2, 3, 4, 6, 8, or 10 WAT and allowing it to grow in competition with tomato the remainder of the season. Tomato shoot dry weight was reduced 23, 7, and 11 g plant−1for each week Palmer amaranth removal was delayed from 0 to 10 WAT in 1996, 1997, and 1998, respectively. Marketable tomato yield ranged from 87,000 to 41,000 kg ha−1for REM of 0 to 10 WAT and 28,000 to 88,000 kg ha−1for EST of 0 to 6 WAT. Percentage of jumbo, large, medium, and cull tomato yields ranged from 49 to 33%, 22 to 31%, 2 to 6%, and 9 to 11%, respectively, for REM of 0 to 10 WAT and 30 to 49%, 38 to 22%, 3 to 2%, and 12 to 9%, respectively, for EST of 0 to 6 WAT. To avoid losses of marketable tomato yield and percentage of jumbo tomato fruit yield, tomato plots must remain free of Palmer amaranth between 3 and 6 WAT. Observed reduction in marketable tomato yield was likely due to competition for light as Palmer amaranth plants exceeded the tomato plant canopy 6 WAT and remained taller than tomato plants for the remainder of the growing season.
Shrub Control in Conservation Reserve Program Lands in Interior Alaska
Authors: Seefeldt Steven S. , Kaspari Phil N. , Conn Jeffery S.
Published: March 2013

In Alaska Conservation Reserve Program (CRP) lands, succession of fields planted with grass and clover to shrubs and small trees is resulting in program compliance problems related to ease of reconversion to crop lands. Standard practice for slowing this succession is mowing every 2 to 3 yr, which does not kill the woody vegetation. A field study was conducted at three sites over 2 yr to determine if 2,4-D (2.2 kg ae ha−1 2-ethylhexyl ester) or triclopyr (2.2 kg ae ha−1 butoxyethyl ester) applied broadcast or 2,4-D (2.2 kg ae ha−1 2,4-D dimethylamine salt) or triclopyr (1.7 kg ae ha−1 triclopyr triethylamine salt) applied with a Diamond Wet Blade™ mower (DWB) would result in longer shrub control compared to mowing. Mowing was conducted at both 15 and 45 cm above ground level and herbicides were applied with the DWB at three rates. Measurements 2 yr after treatment (YAT) confirmed that both herbicides reduced shrub cover about 50% compared to controls. Reduced rates of the herbicides applied with the DWB did not result in decreased shrub control. Grass cover was negatively correlated with shrub cover. Typically, mower height did not alter treatment effects. Treatments had little impact on forb cover and composition 2 YAT, with the exception of fireweed, which was generally reduced where herbicides were applied. Application of 2,4-D and triclopyr does not decrease the frequency of shrub control in CRP lands in Alaska. Use of 2,4-D and triclopyr with or without mowing resulted in no widespread improvement over the current practice of mowing to 15 cm every 2 to 3 yr.
Weed Ecology and Nonchemical Management under Strip-Tillage: Implications for Northern U.S. Vegetable Cropping Systems
Authors: Brainard Daniel C. , Peachey R. Edward , Haramoto Erin R. , Luna John M. , Rangarajan Anusuya
Published: March 2013

In northern U.S. vegetable cropping systems, attempts at no-till (NT) production have generally failed because of poor crop establishment and delayed crop maturity. Strip tillage (ST) minimizes these problems by targeting tillage to the zone where crops are planted while maintaining untilled zones between crop rows, which foster improvements in soil quality. ST has been shown to maintain crop yields while reducing energy use and protecting soils in vegetable crops, including sweet corn, winter squash, snap bean, carrot, and cole crops. Despite potential benefits of ST, weed management remains an important obstacle to widespread adoption. Increased adoption of ST in cropping systems for which effective, low-cost herbicides are either limited (e.g., most vegetable crops) or prohibited (e.g., organic systems) will require integration of multiple cultural, biological, and mechanical approaches targeting weak points in weed life cycles. Weed population dynamics under ST are more complex than under either full-width, conventional tillage (CT) or NT because weed propagules—as well as factors influencing them—can move readily between zones. For example, the untilled zone in ST may provide a refuge for seed predators or a source of slowly mineralized nitrogen, which affects weed seed mortality and germination in the tilled zone. Greater understanding of such interzonal interactions may suggest manipulations to selectively suppress weeds while promoting crop growth in ST systems. Previous studies and recent experiences in ST vegetable cropping systems suggest a need to develop weed management strategies that target distinct zones while balancing crop and soil management tradeoffs. For example, in untilled zones, optimal management may consist of weed-suppressive cover crop mulching, combined with nitrogen exclusion and high-residue cultivation as needed. In contrast, weed management in the tilled zone may benefit from innovations in precision cultivation and flame-weeding technologies. These short-term strategies will benefit from longer-term approaches, including tillage-rotation, crop rotation, and cover cropping strategies, aimed at preventing seed production, promoting seed predation and decay, and preventing buildup of problematic perennial weeds. However, a concerted research effort focused on understanding weed populations as well as testing and refining integrated weed management strategies will be necessary before ST is likely to be widely adopted in vegetable cropping systems without increased reliance on herbicides.