bluuebunny/crossref_metadata_2025 huggingface dataset:
Little ROCK is a ROCK1 pseudogene expressed in human smooth muscle cells
Authors: Montefusco Maria Claudia , Merlo Kristen , Bryan Crystal D , Surks Howard K , Reis Steven E , Mendelsohn Michael E , Huggins Gordon S
Published: April 2010

Background

Sequencing of the human genome has identified numerous chromosome copy number additions and subtractions that include stable partial gene duplications and pseudogenes that when not properly annotated can interfere with genetic analysis. As an example of this problem, an evolutionary chromosome event in the primate ancestral chromosome 18 produced a partial duplication and inversion of rho-associated protein kinase 1 (ROCK1 -18q11.1, 33 exons) in the subtelomeric region of the p arm of chromosome 18 detectable only in humans. ROCK1 and the partial gene copy, which the gene databases also currently call ROCK1, include non-unique single nucleotide polymorphisms (SNPs).

Results

Here, we characterize this partial gene copy of the human ROCK1, termed Little ROCK, located at 18p11.32. Little ROCK includes five exons, four of which share 99% identity with the terminal four exons of ROCK1 and one of which is unique to Little ROCK. In human while ROCK1 is expressed in many organs, Little ROCK expression is restricted to vascular smooth muscle cell (VSMC) lines and organs rich in smooth muscle. The single nucleotide polymorphism database (dbSNP) lists multiple variants contained in the region shared by ROCK1 and Little ROCK. Using gene and cDNA sequence analysis we clarified the origins of two non-synonymous SNPs annotated in the genome to actually be fixed differences between the ROCK1 and the Little ROCK gene sequences. Two additional coding SNPs were valid polymorphisms selectively within Little ROCK. Little ROCK-Green Fluorescent fusion proteins were highly unstable and degraded by the ubiquitin-proteasome system in vitro.

Conclusion

In this report we have characterized Little ROCK (ROCK1P1), a human expressed pseudogene derived from partial duplication of ROCK1. The large number of pseudogenes in the human genome creates significant genetic diversity. Our findings emphasize the importance of taking into consideration pseudogenes in all candidate gene and genome-wide association studies, as well as the need for complete annotation of human pseudogenome.
PKCα expression is a marker for breast cancer aggressiveness
Authors: Lønne Gry Kalstad , Cornmark Louise , Zahirovic Iris Omanovic , Landberg Göran , Jirström Karin , Larsson Christer
Published: April 2010

Background

Protein kinase C (PKC) isoforms are potential targets for breast cancer therapy. This study was designed to evaluate which PKC isoforms might be optimal targets for different breast cancer subtypes.

Results

In two cohorts of primary breast cancers, PKCα levels correlated to estrogen and progesterone receptor negativity, tumor grade, and proliferative activity, whereas PKCδ and PKCε did not correlate to clinicopathological parameters. Patients with PKCα-positive tumors showed poorer survival than patients with PKCα-negative tumors independently of other factors. Cell line studies demonstrated that PKCα levels are high in MDA-MB-231 and absent in T47D cells which proliferated slower than other cell lines. Furthermore, PKCα silencing reduced proliferation of MDA-MB-231 cells. PKCα inhibition or downregulation also reduced cell migration in vitro.

Conclusions

PKCα is a marker for poor prognosis of breast cancer and correlates to and is important for cell functions associated with breast cancer progression.
Sex frequency and sex planning among men who have sex with men in Bangkok, Thailand: implications for pre‐ and post‐exposure prophylaxis against HIV infection
Authors: van Griensven Frits , Thienkrua Warunee , Sukwicha Wichuda , Wimonsate Wipas , Chaikummao Supaporn , Varangrat Anchalee , Mock Philip A
Published: April 2010

Background

Daily HIV antiretroviral pre‐exposure prophylaxis (PrEP) is being evaluated in clinical trials among men who have sex with men (MSM). However, daily PrEP may not be congruent with sexual exposure profiles of MSM. Here, we investigate sex frequency and sex planning to identify and inform appropriate PrEP strategies for MSM.

Methods

We evaluated sex frequency and sex planning in a cohort of HIV‐negative MSM in Bangkok, Thailand. Chi‐squared test was used to compare reports of sex on different weekdays; logistic regression was used to identify predictors of sex frequency and sex planning.

Results

Of 823 MSM (with a mean age of 28.3 years), 86% reported having sex on two days per week or less, and 65% reported their last sex to have been planned. Sex on the weekend (~30%) was more often reported than sex on weekdays (~23%). In multivariate analysis, use of alcohol, erectile dysfunction drugs, group sex, sex with a foreigner, buying and selling sex, and a history of HIV testing were associated with having sex on three days or more per week. Being aged 22 to 29 years, not identifying as homosexual, having receptive anal intercourse, and not engaging in group sex were associated with unplanned sex.

Conclusions

Intermittently dosed PrEP (as opposed to daily) may be a feasible HIV prevention strategy and should be considered for evaluation in clinical trials. Risk factors for sex frequency and sex planning may help to identify those in need for daily PrEP and those who may not be able to take a timely pre‐exposure dose.
Mannosylinositol phosphorylceramide is a major sphingolipid component and is required for proper localization of plasma-membrane proteins inSchizosaccharomyces pombe
Authors: Nakase Mai , Tani Motohiro , Morita Tomotake , Kitamoto Hiroko K. , Kashiwazaki Jun , Nakamura Taro , Hosomi Akira , Tanaka Naotaka , Takegawa Kaoru
Published: April 2010

In Saccharomyces cerevisiae, three classes of sphingolipids contain myo-inositol – inositol phosphorylceramide (IPC), mannosylinositol phosphorylceramide (MIPC) and mannosyldiinositol phosphorylceramide [M(IP)2C]. No fission yeast equivalent of Ipt1p, the inositolphosphotransferase that synthesizes M(IP)2C from MIPC, has been found in the Schizosaccharomyces pombe genome. Analysis of the sphingolipid composition of wild-type cells confirmed that MIPC is the terminal and most abundant complex sphingolipid in S. pombe. Three proteins (Sur1p, Csg2p and Csh1p) have been shown to be involved in the synthesis of MIPC from IPC in S. cerevisiae. The S. pombe genome has three genes (SPAC2F3.01, SPCC4F11.04c and SPAC17G8.11c) that are homologues of SUR1, termed imt1+, imt2+ and imt3+, respectively. To determine whether these genes function in MIPC synthesis in S. pombe, single and multiple gene disruptants were constructed. Single imt disruptants were found to be viable. MIPC was not detected and IPC levels were increased in the triple disruptant, indicating that the three SUR1 homologues are involved in the synthesis of MIPC. GFP-tagged Imt1p, Imt2p and Imt3p localized to Golgi apparatus membranes. The MIPC-deficient mutant exhibited pleiotropic phenotypes, including defects in cellular and vacuolar morphology, and in localization of ergosterols. MIPC seemed to be required for endocytosis of a plasma-membrane-localized amino acid transporter, because sorting of the transporter from the plasma membrane to the vacuole was severely impaired in the MIPC-deficient mutant grown under nitrogen-limiting conditions. These results suggest that MIPC has multiple functions not only in the maintenance of cell and vacuole morphology but also in vesicular trafficking in fission yeast.
Troponin I controls ovulatory contraction of non-striated actomyosin networks in the C. elegans somatic gonad
Authors: Obinata Takashi , Ono Kanako , Ono Shoichiro
Published: April 2010

The myoepithelial sheath of the Caenorhabditis elegans somatic gonad has non-striated actomyosin networks that provide contractile forces during ovulation, a process in which a mature oocyte is expelled from the ovary. Troponin T and troponin C are known regulators of contraction of the myoepithelial sheath. These are two of the three components of the troponin complex that is generally considered as a striated-muscle-specific regulator of actomyosin contraction. Here, we report identification of troponin I as the third component of the troponin complex that regulates ovulatory contraction of the myoepithelial sheath. C. elegans has four genes encoding troponin-I isoforms. We found that tni-1 and unc-27 (also known as tni-2) encode two major troponin-I isoforms in the myoepithelial sheath. Combination of RNA interference and mutation of tni-1 and unc-27 resulted in loss of the troponin-I protein in the gonad and caused sterility due to defective contraction of the myoepithelial sheath. Troponin-I-depleted gonads were hypercontracted, which is consistent with the function of troponin I as an inhibitor of actomyosin contraction. Troponin I was associated with non-striated actin networks in a tropomyosin-dependent manner. Our results demonstrate that troponin I regulates contraction of non-striated actomyosin networks and is an essential cytoskeletal component of the C. elegans reproductive system.
Stability elements in the LRP6 cytoplasmic tail confer efficient signalling upon DIX-dependent polymerization
Authors: Metcalfe Ciara , Mendoza-Topaz Carolina , Mieszczanek Juliusz , Bienz Mariann
Published: April 2010

Wnt/β-catenin signalling controls cell fates in development, tissue homeostasis and cancer. Wnt binding to Frizzled receptors triggers recruitment of Dishevelled to the plasma membrane and formation of a signalosome containing the LRP5/6 co-receptor, whose cytoplasmic tail (ctail) thus becomes phosphorylated at multiple PPP(S/T)Px(S/T) motifs. These then directly inhibit GSK3β, which results in β-catenin accumulation and signalling. Here, we revisit previous epistasis experiments, and show that Dishevelled signals through LRP5/6 in human cells and Drosophila embryos. To recapitulate this signalling event, and to define its functional elements, we fused the Dishevelled DIX domain to the LRP6 ctail, which forms cytoplasmic signalosomes with potent signalling activity mediated by its PPP(S/T)Px(S/T) motifs. Their phosphorylation and activity depends critically on DIX-mediated polymerization, and on multiple stability elements in the LRP6 ctail, including the T1479 epitope upstream of the membrane-proximal PPP(S/T)Px(S/T) motif. Thus, stable polymerization emerges as a key principle underlying the function of Dishevelled-dependent signalosomes.
Iloperidone for the Treatment of Schizophrenia
Authors: Marino Jehan , Caballero Joshua
Published: April 2010

OBJECTIVE:

To review the pharmacology, pharmacokinetics, efficacy, and safety data of iloperidone for the treatment of schizophrenia.

DATA SOURCES:

Data were selected by searching Pre-MEDLINE, MEDLINE, and International Pharmaceutical Abstracts (1966-January 2010). Abstracts, scientific posters, and unpublished data provided by the manufacturer in the English language were also assessed.

STUDY SELECTION AND DATA EXTRACTION:

All published data including pharmacologic, pharmacokinetic, pharmacodynamic, and clinical studies related to iloperidone were considered for inclusion. Selected studies included randomized controlled trials, abstracts, and posters presented at national scientific meetings providing pertinent data. data synthesis: Iloperidone is a benzisoxazole phenylethanone with a higher affinity for serotonin-2a than dopamine-2 receptors. The recommended therapeutic total daily dose is 12-24 mg divided in 2 doses titrated over 1 week to avoid orthostasis. Acute, 6-week, randomized, placebo-controlled, and active-controlled studies demonstrated iloperidone's efficacy in reducing psychotic symptoms according to changes in the total positive and negative symptom scale (PANSS-T) score from baseline. A long-term maintenance trial demonstrated similar efficacy with haloperidol in preventing time to relapse. Pharmacogenomic studies reported possible single nucleotide polymorphisms related to QT interval prolongation and efficacy with iloperidone. Common adverse effects included dizziness, dry mouth, and sustained orthostasis occurring more frequently with higher doses. Weight gain is possible at any dose. Additionally, studies showed that QTc interval prolongation may be dose related. The incidence of extrapyramidal symptoms appears to be low across all dosage ranges; however, akathisia may be more frequent with higher doses.

CONCLUSIONS:

Iloperidone demonstrated efficacy in acute exacerbations and long-term maintenance in adults with schizophrenia. Caution may be warranted in elderly patients and patients with cardiac disease, due to orthostasis. Further studies regarding pharmacogenomic testing related to the drug's efficacy and tolerability are needed to justify its routine use in practice.
Assessment of Changes in Utilization of Health-Care Services after Implementation of a Prior Authorization Policy for Atypical Antipsychotic Agents
Authors: Walthour Amy , Seymour Lynne , Tackett Randall , Perri Matthew
Published: April 2010

BACKGROUND:

In 2004, the Georgia Medicaid program implemented a prior authorization (PA) policy for certain atypical antipsychotic agents, resulting in an average savings of $2.7 million per year.

OBJECTIVE:

To determine whether implementation of a PA policy for atypical antipsychotic drugs increased health-care utilization in the Georgia Medicaid program from July 2003 to April 2006.

METHODS:

A single cohort observational study employing segmented regression and time series analysis was conducted to determine health-care services utilization, including emergency department (ED) visits, outpatient office visits, hospital admissions, and length of stay (LOS). Study subjects included continuously eligible adult Georgia Medicaid recipients with a schizophrenia-related diagnosis and documented use of an atypical antipsychotic medication (N = 12,120). Where applicable, analysis of a noncontinuously eligible population was also performed to investigate disenrollment bias in study results.

RESULTS:

A significant decline in post-policy trend for the average number of ED visits (absolute difference −0.042 per member per month (PMPM); relative difference −20.92%) and average number of hospital admissions PMPM (absolute difference −0.010 PMPM; relative difference −22.27%) was observed at the end of the study period. Baseline and pre-policy trends were found to be significant predictors for both endpoints. Significant models were not identified for average outpatient office visits PMPM or average LOS per admission.

CONCLUSIONS:

In contrast to other published studies on PA for atypical antipsychotics, patient outcomes improved after the initiation of the policy. To the extent that medical utilization reflects patient health outcomes and health status, the results of this study indicate that the PA program has potentially improved the health of schizophrenic patients in Georgia and lowered program costs.
Bowing in the right direction: Hiland Mountain Correctional Center women's string orchestra programme
Authors: Warfield Duane
Published: April 2010

The Hiland Mountain Correctional Center, a 400-bed facility for multi-level adult female offenders in Eagle River, Alaska, offers a unique educational programme to its prisoners: an orchestra. Founded in 2003, by volunteer Pati Crofut, orchestra membership grew from eight to 22 female
offenders between 2003 and 2009. Crofut has devoted her time and energy to the group and helped initiate the ensemble along with a non-profit organization to promote the programme, Arts on the Edge. Through the efforts of Crofut, the prison and the hired conductors, the all-female orchestra
performs twice a year in the facility and the experiences provide opportunities for the inmates to appreciate music. Primary source data included interviews with Pati Crofut and Gabrielle Willis, one of the orchestra conductors. This article offers suggestions for how this programme may guide
future community music programmes and be a model for similar programmes in progress.
Singing with conviction: New Zealand prisons and Maori populations
Authors: Menning Nancy
Published: April 2010

This article describes the Singing with Conviction pilot project (SWCPP) facilitated by Arts Access Aotearoa in the New Zealand prison system in 200405. The pilot project was modelled in part on competitive prison singing groups in South Africa, with adaptations made for the New Zealand cultural context. The analysis proceeds in two steps. First, I describe the pilot project, placing it in relation to a more-encompassing arts strategy for marginalized prison populations. Second, I explore ethnic dimensions of the SWCPP related to New Zealand's Maori population, quantifying the disproportionate representation of Maori persons in New Zealand's prisons and summarizing recent efforts to incorporate indigenous Maori modes of punishment and dispute resolution within New Zealand's criminal justice system. I conclude with general reflections on how a prison choir project might better serve a bicultural population.
If I Cry for You. Turning unspoken trauma into song and musical theatre
Authors: Palidofsky Meade
Published: April 2010

Through a carefully guided process of sharing personal stories, Storycatchers Theatre (the new name for Music Theatre Workshop) has prepared young people to make more positive life choices through the process of writing, producing and performing original musical theatre since 1984.
The Fabulous Females program for girls incarcerated at the Illinois Youth Center (IYC) in Warrenville, Illinois, began in 2002. Fabulous Females provides a safe environment for girls to reveal past traumatic experiences, often of extreme physical and sexual abuse, helping them connect their
emotional reactions to subsequent negative choices and incarceration. Through the year-long process, these painful stories take on a life of their own as the girls translate them into scenes and song. Empowered by their creativity, they begin to heal and to believe in their capacity to move
on with their lives. This article summarizes and highlights the amazing and powerful work of Storycatchers Theatre.
Cim ar Chim, Step by Step Community music programme in an Irish probation centre: A personal reflection
Authors: Tiernan Julie
Published: April 2010

Proactive instruction and alternative education have progressively become the schooling of choice for many non-traditional learners in Ireland. Community training, probation and Traveller support centers endeavour to take an existing curriculum and tailor it to such learners' needs.
One community based education and training centre funded by the Probation and Welfare Services, Cim ar Chim, is located on the north side of Limerick city.When built in 1973, it was considered to be a state-of-the-art area. Today, however, this area has been named the murder capital
of Western Europe; violence and crime rates are high while 50 per cent of the population is under 24 (Cusack 2006). This article offers a reflection on the experience of a tutor and community musician working in this environment. I hope to demonstrate how up-skilling the existing staff and
increasing student-to-staff/tutor ratio in addition to other factors dramatically changed the dynamic within this place of learning.
Engaging Scottish young offenders in education through music and art
Authors: Anderson Kirstin , Overy Katie
Published: April 2010

This study examined music and art classes as a way to engage young offenders in education, and to see if such engagement had an effect on their further participation in education, self-esteem, self-control, behaviour and literacy skills. The arts are often discussed as being an inviting
and safe method of entry for young offenders who may have had negative experiences with previous education in their formative years. Fourteen young offenders at Her Majesty's Young Offender Institution (HM YOI) Polmont in Scotland voluntarily participated in this ten-week study. Participants
were divided into three groups: music, art and a control education group. They completed pre- and post-interviews and measures that examined their emotions, self-esteem, self-control and literacy skills. Behavioural reports and enrollment in education courses were reviewed for three months
before and after the project. Results indicated increased engagement with education during and after the project for individuals in the music and art groups.
Re-sounding: Refuge and reprise in a prison choral community
Authors: Roma Catherine
Published: April 2010

This article examines a men's prison chorus in a close security Ohio prison. The purpose of the project is, broadly, to understand how a men's prison choral community (UMOJA) impacts inmate self-perception, intra-group relationships and external connections. These external connections
include choral recordings where the proceeds from the CD sales benefit charities of the inmates' choosing. This component helps the prisoners connect with the larger society outside prison. To this end, the following research questions were investigated: (1) How does the inmates' participation
in UMOJA affect their experience of daily life in prison including their self perception? (2) How does musical performance, especially of inmate-composed choral repertoire, affect the choir as a community (intra-group, relationships, external connections)? Throughout the article the men's
names have been changed to protect their privacy.
Hotel Two Rooms: The practice of adaptation, projection and play in performance
Authors: Hind Claire
Published: April 2010

This article discusses the processes of performance practice in a two-to-two context of both rehearsal and live performance. The work discusses the project Hotel Two Rooms where two participants were invited to a hotel room to adapt a short scene from a movie and perform to a
live feed for an installation. The writing explicates practice through the theory of play and talks through a contemporary notion of adaptation for performance works.
Reviews
Authors: Memou Antigoni , Adil Alev , Kinsman Margaret , Paul Richard , Smyth Diane
Published: April 2010

You've been framed Disciplinary Frame: Photographic Truths and the Capture of Meaning, John Tagg (2009) Minneapolis, London: University of Minnesota Press, 392 pp., Hardback, ISBN 0816642877, 51.50, Paperback, ISBN 0816642885, 15.67

Becoming photographic Photography,
Cinema, Memory: The Crystal Image of Time, Damian Sutton (2009) Minnesota, University of Minnesota Press, 296 pp., ISBN 9780816647392, Paperback, 15.50

The lure of the crime scene Lacan at the Scene, Henry Bond (2009) Cambridge, Mass.: MIT Press, 256 pp., ISBN 0262013428,
Hardback, 14

Re rereading Camera Lucida Photography Degree Zero, Reflections on Roland Barthes's Camera Lucida, Geoffrey Batchen (ed.) (2009) Massachusetts: MIT Press, pp. 320, ISBN 026201358, Hardback, 22.95

Conference Report Humanising Photography, Durham Centre
for Advanced Photography Studies (organized in partnership with Autograph ABP), 2527 September 2009
Cognitive Impairment in Pain through Amygdala-Driven Prefrontal Cortical Deactivation
Authors: Ji Guangchen , Sun Hao , Fu Yu , Li Zhen , Pais-Vieira Miguel , Galhardo Vasco , Neugebauer Volker
Published: April 2010

Cognitive deficits such as impaired decision-making can be a consequence of persistent pain. Normal functions of the intact amygdala and prefrontal cortex are required for emotion-based decision-making that relies on the ability to assess risk, attribute value, and identify advantageous strategies. We tested the hypothesis that pain-related cognitive deficits result from amygdala-driven impairment of medial prefrontal cortical (mPFC) function. To do this, we used electrophysiological single-unit recordingsin vivo, patch clamp in brain slices, and various behavioral assays to show that increased neuronal activity in the amygdala in an animal model of arthritis pain was accompanied by decreased mPFC activation and impaired decision-making. Furthermore, pharmacologic inhibition (with a corticotropin-releasing factor 1 receptor antagonist) of pain-related hyperactivity in the basolateral amygdala (BLA), but not central amygdala (CeA), reversed deactivation of mPFC pyramidal cells and improved decision-making deficits. Pain-related cortical deactivation resulted from a shift of balance between inhibitory and excitatory synaptic transmission. Direct excitatory transmission to mPFC pyramidal cells did not change in the pain model, whereas polysynaptic inhibitory transmission increased. GABAergic transmission was reduced by non-NMDA receptor antagonists, suggesting that synaptic inhibition was glutamate driven. The results are consistent with a model of BLA-driven feedforward inhibition of mPFC neurons. In contrast to the differential effects of BLA versus CeA hyperactivity on cortical-cognitive functions, both amygdala nuclei modulate emotional-affective pain behavior. Thus, this study shows that the amygdala contributes not only to emotional-affective but also cognitive effects of pain. The novel amygdalo-cortical pain mechanism has important implications for our understanding of amygdala functions and amygdalo-cortical interactions.
Impaired Head Direction Cell Representation in the Anterodorsal Thalamus after Lesions of the Retrosplenial Cortex
Authors: Clark Benjamin J. , Bassett Joshua P. , Wang Sarah S. , Taube Jeffrey S.
Published: April 2010

The retrosplenial cortex (RSP), a brain region frequently linked to processes of spatial navigation, contains neurons that discharge as a function of a rat's head direction (HD). HD cells have been identified throughout the limbic system including the anterodorsal thalamus (ADN) and postsubiculum (PoS), both of which are reciprocally connected to the RSP. The functional relationship between HD cells in the RSP and those found in other limbic regions is presently unknown, but given the intimate connectivity between the RSP and regions such as the ADN and PoS, and the reported loss of spatial orientation in rodents and humans with RSP damage, it is likely that the RSP plays an important role in processing the limbic HD signal. To test this hypothesis, we produced neurotoxic or electrolytic lesions of the RSP and recorded HD cells in the ADN of female Long–Evans rats. HD cells remained present in the ADN after RSP lesions, but the stability of their preferred firing directions was significantly reduced even in the presence of a salient visual landmark. Subsequent tests revealed that lesions of the RSP moderately impaired landmark control over the cells' preferred firing directions, but spared the cells directional stability when animals were required to update their orientation using self-movement cues. Together, these results suggest that the RSP plays a prominent role in processing landmark information for accurate HD cell orientation and may explain the poor directional sense in humans that follows damage to the RSP.
Bicuculline-Sensitive Primary Afferent Depolarization Remains after Greatly Restricting Synaptic Transmission in the Mammalian Spinal Cord
Authors: Shreckengost Jacob , Calvo Jorge , Quevedo Jorge , Hochman Shawn
Published: April 2010

Primary afferent neurotransmission is the fundamental first step in the central processing of sensory stimuli. A major mechanism producing afferent presynaptic inhibition is via a channel-mediated depolarization of their intraspinal terminals which can be recorded extracellularly as a dorsal root potential (DRP). Based on measures of DRP latency it has been inferred that this primary afferent depolarization (PAD) of low-threshold afferents is mediated by minimally trisynaptic pathways with GABAergic interneurons forming last-order axoaxonic synapses onto afferent terminals. We used anin vitrorat spinal cord preparation under conditions that restrict synaptic transmission to test whether more direct low-threshold pathways can produce PAD. Mephenesin or high divalent cation solutions were used to limit oligosynaptic transmission. Recordings of synaptic currents in dorsal horn neurons and population synaptic potentials in ventral roots provided evidence that conventional transmission was chiefly restricted to monosynaptic actions. Under these conditions, DRP amplitude was largely unchanged but with faster time to peak and reduced duration. Similar results were obtained following stimulation of peripheral nerves. Even following near complete block of transmission with high Mg2+/low Ca2+-containing solution, the evoked DRP was reduced but not blocked. In comparison, in nominally Ca2+-free or EGTA-containing solution, the DRP was completely blocked confirming that Ca2+entry mediated synaptic transmission is required for DRP genesis. Overall these results demonstrate that PAD of low-threshold primary afferents can occur by more direct synaptic mechanisms, including the possibility of direct negative-feedback or nonspiking dendroaxonic pathways.
α5GABAAReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory
Authors: Martin Loren J. , Zurek Agnieszka A. , MacDonald John F. , Roder John C. , Jackson Michael F. , Orser Beverley A.
Published: April 2010

Synaptic plasticity, which is the neuronal substrate for many forms of hippocampus-dependent learning, is attenuated by GABA type A receptor (GABAAR)-mediated inhibition. The prevailing notion is that a synaptic or phasic form of GABAergic inhibition regulates synaptic plasticity; however, little is known about the role of GABAAR subtypes that generate a tonic or persistent inhibitory conductance. We studied the regulation of synaptic plasticity by α5 subunit-containing GABAARs (α5GABAARs), which generate a tonic inhibitory conductance in CA1 pyramidal neurons using electrophysiological recordings of field and whole-cell potentials in hippocampal slices from both wild-type and null mutant mice for the α5 subunit of the GABAAR (Gabra5−/−mice). In addition, the strength of fear-associated memory was studied. The results showed that α5GABAAR activity raises the threshold for induction of long-term potentiation in a highly specific band of stimulation frequencies (10–20 Hz) through mechanisms that are predominantly independent of inhibitory synaptic transmission. The deletion or pharmacological inhibition of α5GABAARs caused no change in baseline membrane potential or input resistance but increased depolarization during 10 Hz stimulation. The encoding of hippocampus-dependent memory was regulated by α5GABAARs but only under specific conditions that generate moderate but not robust forms of fear-associated learning. Thus, under specific conditions, α5GABAAR activity predominates over synaptic inhibition in modifying the strength of both synaptic plasticityin vitroand certain forms of memoryin vivo.
During Visual Word Recognition, Phonology Is Accessed within 100 ms and May Be Mediated by a Speech Production Code: Evidence from Magnetoencephalography: Figure 1.
Authors: Wheat Katherine L. , Cornelissen Piers L. , Frost Stephen J. , Hansen Peter C.
Published: April 2010

Debate surrounds the precise cortical location and timing of access to phonological information during visual word recognition. Therefore, using whole-head magnetoencephalography (MEG), we investigated the spatiotemporal pattern of brain responses induced by a masked pseudohomophone priming task. Twenty healthy adults read target words that were preceded by one of three kinds of nonword prime: pseudohomophones (e.g.,brein–BRAIN), where four of five letters are shared between prime and target, and the pronunciation is the same; matched orthographic controls (e.g.,broin–BRAIN), where the same four of five letters are shared between prime and target but pronunciation differs; and unrelated controls (e.g.,lopus–BRAIN), where neither letters nor pronunciation are shared between prime and target. All three priming conditions induced activation in the pars opercularis of the left inferior frontal gyrus (IFGpo) and the left precentral gyrus (PCG) within 100 ms of target word onset. However, for the critical comparison that reveals a processing difference specific to phonology, we found that the induced pseudohomophone priming response was significantly stronger than the orthographic priming response in left IFG/PCG at ∼100 ms. This spatiotemporal concurrence demonstrates early phonological influences during visual word recognition and is consistent with phonological access being mediated by a speech production code.
Emotional Processing in a Salient Motion Context: Integration of Motion and Emotion in Both V5/hMT+ and the Amygdala
Authors: Hindi Attar Catherine , Müller Matthias M. , Andersen Søren K. , Büchel Christian , Rose Michael
Published: April 2010

Recent studies have suggested that the extent to which primary task demands draw on attentional resources determines whether or not task-irrelevant emotional stimuli are processed. Another important factor that can bias task-relevant and task-irrelevant stimulus competition is the bottom-up factor of stimulus salience. Here, we investigated the effect of stimulus salience associated with a primary motion task on the processing of emotional face distractors. Faces of different emotional valences were presented within a context of randomly moving dots. Subjects had to detect short intervals of coherent motion while ignoring the background faces. Task salience was manipulated by the level of motion coherence of the dots with high motion coherence being associated with high salience. Using functional magnetic resonance imaging, we show that emotional faces, compared with neutral faces, more strongly interfered with the primary task, as reflected in significant signal decreases in task-related motion area V5/hMT+. In addition, these faces elicited significant signal increases in the left amygdala. Most importantly, task salience was found to further increase amygdala's activity when presented together with an emotional face. Our data support a more general role of the amygdala as a behavioral relevance detector, which flexibly integrates behavioral relevant, salient context information to decode the emotional content of a visual scene.
Focal Cortical Infarcts Alter Intrinsic Excitability and Synaptic Excitation in the Reticular Thalamic Nucleus
Authors: Paz Jeanne T. , Christian Catherine A. , Parada Isabel , Prince David A. , Huguenard John R.
Published: April 2010

Focal cortical injuries result in death of cortical neurons and their efferents and ultimately in death or damage of thalamocortical relay (TCR) neurons that project to the affected cortical area. Neurons of the inhibitory reticular thalamic nucleus (nRT) receive excitatory inputs from corticothalamic and thalamocortical axons and are thus denervated by such injuries, yet nRT cells generally survive these insults to a greater degree than TCR cells. nRT cells inhibit TCR cells, regulate thalamocortical transmission, and generate cerebral rhythms including those involved in thalamocortical epilepsies. The survival and reorganization of nRT after cortical injury would determine recovery of thalamocortical circuits after injury. However, the physiological properties and connectivity of the survivors remain unknown. To study possible alterations in nRT neurons, we used the rat photothrombosis model of cortical stroke. Usingin vitropatch-clamp recordings at various times after the photothrombotic injury, we show that localized strokes in the somatosensory cortex induce long-term reductions in intrinsic excitability and evoked synaptic excitation of nRT cells by the end of the first week after the injury. We find that nRT neurons in injured rats show (1) decreased membrane input resistance, (2) reduced low-threshold calcium burst responses, and (3) weaker evoked excitatory synaptic responses. Such alterations in nRT cellular excitability could lead to loss of nRT-mediated inhibition in relay nuclei, increased output of surviving TCR cells, and enhanced thalamocortical excitation, which may facilitate recovery of thalamic and cortical sensory circuits. In addition, such changes could be maladaptive, leading to injury-induced epilepsy.
Nicotinic Acetylcholine Receptors in the Mesolimbic Pathway: Primary Role of Ventral Tegmental Area α6β2* Receptors in Mediating Systemic Nicotine Effects on Dopamine Release, Locomotion, and Reinforcement
Authors: Gotti Cecilia , Guiducci Stefania , Tedesco Vincenzo , Corbioli Silvia , Zanetti Lara , Moretti Milena , Zanardi Alessio , Rimondini Roberto , Mugnaini Manolo , Clementi Francesco , Chiamulera Christian , Zoli Michele
Published: April 2010

α6* nicotinic acetylcholine receptors (nAChRs) are highly and selectively expressed by mesostriatal dopamine (DA) neurons. These neurons are thought to mediate several behavioral effects of nicotine, including locomotion, habit learning, and reinforcement. Yet the functional role of α6* nAChRs in midbrain DA neurons is mostly unknown. The aim of this study was to determine the composition andin vivofunctional role of α6* nAChR in mesolimbic DA neurons of male rats. Immunoprecipitation and immunopurification techniques coupled with cell-specific lesions showed that the composition of α6* nAChR in the mesostriatal system is heterogeneous, with (non-α4)α6β2* being predominant in the mesolimbic pathway and α4α6β2* in the nigrostriatal pathway. We verified whether α6* receptors mediate the systemic effects of nicotine on the mesolimbic DA pathway by perfusing the selective antagonists α-conotoxin MII (CntxMII) (α3/α6β2* selective) or α-conotoxin PIA (CntxPIA) (α6β2* selective) into ventral tegmental area (VTA). The intra-VTA perfusion of CntxMII or CntxPIA markedly decreased systemic nicotine-elicited DA release in the nucleus accumbens and habituated locomotion; the intra-VTA perfusion of CntxMII also decreased the rate of nicotine infusion in the maintenance phase of nicotine, but not of food, self-administration. Overall, the results of these experiments show that the α6β2* nAChRs expressed in the VTA are necessary for the effects of systemic nicotine on DA neuron activity and DA-dependent behaviors such as locomotion and reinforcement, and suggest that α6β2*-selective compounds capable of crossing the blood–brain barrier may affect the addictive properties of nicotine and therefore be useful in the treatment of tobacco dependence.
Metabotropic Glutamate Receptor 1 Mediates the Electrophysiological and Toxic Actions of the Cycad Derivative β-N-Methylamino-l-Alanine on Substantia Nigra Pars Compacta DAergic Neurons
Authors: Cucchiaroni Maria Letizia , Viscomi Maria Teresa , Bernardi Giorgio , Molinari Marco , Guatteo Ezia , Mercuri Nicola B.
Published: April 2010

Amyotrophic lateral sclerosis–Parkinson dementia complex (ALS-PDC) is a neurodegenerative disease with ALS, parkinsonism, and Alzheimer's symptoms that is prevalent in the Guam population. β-N-Methylamino alanine (BMAA) has been proposed as the toxic agent damaging several neuronal types in ALS-PDC, including substantia nigra pars compacta dopaminergic (SNpc DAergic) neurons. BMAA is a mixed glutamate receptor agonist, but the specific pathways activated in DAergic neurons are not yet known. We combined electrophysiology, microfluorometry, and confocal microscopy analysis to monitor membrane potential/current, cytosolic calcium concentration ([Ca2+]i) changes, cytochrome-c(cyt-c) immunoreactivity, and reactive oxygen species (ROS) production induced by BMAA. Rapid toxin applications caused reversible membrane depolarization/inward current and increase of firing rate and [Ca2+]iin DAergic neurons. The inward current (IBMAA) was mainly mediated by activation of metabotropic glutamate receptor 1 (mGluR1), coupled to transient receptor potential (TRP) channels, and to a lesser extent, AMPA receptors. Indeed, mGluR1 (CPCCOEt) and TRP channels (SKF 96365; Ruthenium Red) antagonists reducedIBMAA, and a small component ofIBMAAwas reduced by the AMPA receptor antagonist CNQX. Calcium accumulation was mediated by mGluR1 but not by AMPA receptors. Application of a low concentration of NMDA potentiated the BMAA-mediated calcium increase. Prolonged exposure to BMAA caused significant modifications of membrane properties, calcium overload, cell shrinkage, massive cyt-crelease into the cytosol and ROS production. In SNpc GABAergic neurons, BMAA activated only AMPA receptors. Our study identifies the mGluR1-activated mechanism induced by BMAA that may cause the neuronal degeneration and parkinsonian symptoms seen in ALS-PDC. Moreover, environmental exposure to BMAA might possibly also contribute to idiopathic PD.
Use-Dependent and Error-Based Learning of Motor Behaviors
Authors: Diedrichsen Jörn , White Olivier , Newman Darren , Lally Níall
Published: April 2010

Human motor behavior is constantly adapted through the process of error-based learning. When the motor system encounters an error, its estimate about the body and environment will change, and the next movement will be immediately modified to counteract the underlying perturbation. Here, we show that a second mechanism, use-dependent learning, simultaneously changes movements to become more similar to the last movement. In three experiments, participants made reaching movements toward a horizontally elongated target, such that errors in the initial movement direction did not have to be corrected. Along this task-redundant dimension, we were able to induce use-dependent learning by passively guiding movements in a direction angled by 8° from the previous direction. In a second study, we show that error-based and use-dependent learning can change motor behavior simultaneously in opposing directions by physically constraining the direction of active movements. After removal of the constraint, participants briefly exhibit an error-based aftereffect against the direction of the constraint, followed by a longer-lasting use-dependent aftereffect in the direction of the constraint. In the third experiment, we show that these two learning mechanisms together determine the solution the motor system adopts when learning a motor task.
Cholecystokinin Facilitates Glutamate Release by Increasing the Number of Readily Releasable Vesicles and Releasing Probability
Authors: Deng Pan-Yue , Xiao Zhaoyang , Jha Archana , Ramonet David , Matsui Toshimitsu , Leitges Michael , Shin Hee-Sup , Porter James E. , Geiger Jonathan D. , Lei Saobo
Published: April 2010

Cholecystokinin (CCK), a neuropeptide originally discovered in the gastrointestinal tract, is abundantly distributed in the mammalian brains including the hippocampus. Whereas CCK has been shown to increase glutamate concentration in the perfusate of hippocampal slices and in purified rat hippocampal synaptosomes, the cellular and molecular mechanisms whereby CCK modulates glutamatergic function remain unexplored. Here, we examined the effects of CCK on glutamatergic transmission in the hippocampus using whole-cell recordings from hippocampal slices. Application of CCK increased AMPA receptor-mediated EPSCs at perforant path-dentate gyrus granule cell, CA3-CA3 and Schaffer collateral–CA1 synapses without effects at mossy fiber-CA3 synapses. CCK-induced increases in AMPA EPSCs were mediated by CCK-2 receptors and were not modulated developmentally and transcriptionally. CCK reduced the coefficient of variation and paired-pulse ratio of AMPA EPSCs suggesting that CCK facilitates presynaptic glutamate release. CCK increased the release probability and the number of readily releasable vesicles with no effects on the rate of recovery from vesicle depletion. CCK-mediated increases in glutamate release required the functions of phospholipase C, intracellular Ca2+release and protein kinase Cγ. CCK released endogenously from hippocampal interneurons facilitated glutamatergic transmission. Our results provide a cellular and molecular mechanism to explain the roles of CCK in the brain.
DMob4/Phocein Regulates Synapse Formation, Axonal Transport, and Microtubule Organization
Authors: Schulte Joost , Sepp Katharine J. , Jorquera Ramon A. , Wu Chaohong , Song Yun , Hong Pengyu , Littleton J. Troy
Published: April 2010

The monopolar spindle-one-binder (Mob) family of kinase-interacting proteins regulate cell cycle and cell morphology, and their dysfunction has been linked to cancer. Models for Mob function are primarily based on studies of Mob1 and Mob2 family members in yeast. In contrast, the function of the highly conserved metazoan Phocein/Mob3 subfamily is unknown. We identified theDrosophilaPhocein homolog (DMob4) as a regulator of neurite branching in a genome-wide RNA interference screen for neuronal morphology mutants. To further characterize DMob4, we generated null and hypomorphic alleles and performedin vivocell biological and physiological analysis. We find that DMob4 plays a prominent role in neural function, regulating axonal transport, membrane excitability, and organization of microtubule networks.DMob4mutant neuromuscular synapses also show a profound overgrowth of synaptic boutons, similar to knownDrosophilaendocytotic mutants. DMob4 and human Phocein are >80% identical, and the lethality ofDMob4mutants can be rescued by a humanphoceintransgene, indicating a conservation of function across evolution. These findings suggest a novel role for Phocein proteins in the regulation of axonal transport, neurite elongation, synapse formation, and microtubule organization.
False Messiah
Authors: Roberts John H.
Published: April 2010

In closely connected studies Tassilo Erhardt and Michael Marissen have suggested that Handel's Messiah is fundamentally anti-Jewish. Erhardt, who based his conclusions on books thought to have been in the library of Charles Jennens, compiler of the Messiah libretto, argues that the text was intended as a defense of orthodox Christianity against Judaism as well as Deism; Marissen contends it “was designed to teach contempt for Jews and Judaism.” Closer examination of the theological literature of Jennens's day shows that the theories of both scholars are founded on selective and tendentious reading of the sources. Marissen's further claim that Handel consciously reinforced the libretto's supposed anti-Jewish connotations by means of motivic symbolism, orchestration, and chorale quotations rests on misconceptions about the composer's style. Jennens probably conceived Messiah not to counter either Deism or Judaism but to inspire his Christian audience to greater devotion. The preference he gave to Old Testament prophecy over New Testament narrative reflects a tacit contemporary prohibition against direct representation of Christ in the English theater.
The Testimonial Aesthetics of Different Trains
Authors: Wlodarski Amy Lynn
Published: April 2010

Often praised as an exceptional artistic response to the Holocaust, Steve Reich's Different Trains adopts a documentary approach to Holocaust representation in which Reich assembled short excerpts from three survivor testimonies and published transcriptions of their accounts in his libretto for the work. This article explores the consequences that arise when fragments from very emotional testimonies are recast as purportedly unmediated documentary. The authority attributed to this sort of historical narrative has come under scrutiny in the field of Holocaust studies, in which it is called “secondary witness”—an intellectual interpretation of survivor testimonies advanced without the author revealing his or her own subjective standpoint or scholarly agenda. I argue that Reich's use of the voices of the survivors, Paul, Rachel, and Rachella, constitutes a form of secondary witness. Analysis of the original sources reveals that as Reich worked with extracts from the testimonies, in some cases his composition took on the aesthetics of the original testimonies, yet in other cases, he altered meaning and tone and even misheard certain phrases, producing transcription errors that reframed key moments by substituting his account of the Holocaust for that of the primary witness. Such revelations prompt reevaluation of the moral and political success that has been claimed for Different Trains, since the compositional process could never have been as objective and self-effacing as Reich and his critics suggest.