bluuebunny/crossref_metadata_2025 huggingface dataset:
Extending food deprivation reverses the short-term lipolytic response to fasting: role of the triacylglycerol/fatty acid cycle
Authors: Weber Jean-Michel , Reidy Shannon P.
Published: April 2012

The effects of short-term food deprivation on lipid metabolism are well documented, but little is known about prolonged fasting. This study monitored the kinetics of glycerol (rate of appearance, Ra glycerol) and non-esterified fatty acids (Ra NEFA) in fasting rabbits. Our goals were to determine whether lipolysis is stimulated beyond values seen for short-term fasting, and to characterize the roles of primary (intracellular) and secondary (with transit through the circulation) triacylglycerol/fatty acid cycling (TAG/FA cycling) in regulating fatty acid allocation to oxidation or re-esterification. Ra glycerol (9.62±0.72 to 15.29±0.96 μmol kg–1 min–1) and Ra NEFA (18.05±2.55 to 31.25±1.93 μmol kg–1 min–1) were stimulated during the first 2 days of fasting, but returned to baseline after 4 days. An initial increase in TAG/FA cycling was followed by a reduction below baseline after 6 days without food, with primary and secondary cycling contributing to these responses. We conclude that the classic activation of lipolysis caused by short-term fasting is abolished when food deprivation is prolonged. High rates of re-esterification may become impossible to sustain, and TAG/FA cycling could decrease to reduce its cost to 3% of total energy expenditure. Throughout prolonged fasting, fatty acid metabolism gradually shifts towards increased oxidation and reduced re-esterification. Survival is achieved by pressing fuel selection towards the fatty acid dominance of energy metabolism and by slowing substrate cycles to assist metabolic suppression. However, TAG/FA cycling remains active even after prolonged fasting, suggesting that re-esterification is a crucial mechanism that cannot be stopped without harmful consequences.
Divalent metal (Ca, Cd, Mn, Zn) uptake and interactions in the aquatic insectHydropsyche sparna
Authors: Poteat Monica D. , Díaz-Jaramillo Mauricio , Buchwalter David B.
Published: April 2012

Despite their ecological importance and prevalent use as ecological indicators, the trace element physiology of aquatic insects remains poorly studied. Understanding divalent metal transport processes at the water–insect interface is important because these metals may be essential (e.g. Ca), essential and potentially toxic (e.g. Zn) or non-essential and toxic (e.g. Cd). We measured accumulation kinetics of Zn and Cd across dissolved concentrations ranging 4 orders of magnitude and examined interactions with Ca and Mn in the caddisfly Hydropsyche sparna. Here, we provide evidence for at least two transport systems for both Zn and Cd, the first of which operates at concentrations below 0.8 μmol l–1 (and is fully saturable for Zn). We observed no signs of saturation of a second lower affinity transport system at concentrations up to 8.9 μmol l–1 Cd and 15.3 μmol l–1 Zn. In competition studies at 0.6 μmol l–1 Zn and Cd, the presence of Cd slowed Zn accumulation by 35% while Cd was unaffected by Zn. At extreme concentrations (listed above), Cd accumulation was unaffected by the presence of Zn whereas Zn accumulation rates were reduced by 58%. Increasing Ca from 31.1 μmol l–1 to 1.35 mmol l–1 resulted in only modest decreases in Cd and Zn uptake. Mn decreased adsorption of Cd and Zn to the integument but not internalization. The L-type Ca2+ channel blockers verapamil and nifedipine and the plasma membrane Ca2+-ATPase inhibitor carboxyeosin had no influence on Ca, Cd or Zn accumulation rates, while Ruthenium Red, a Ca2+-ATPase inhibitor, significantly decreased the accumulation of all three in a concentration-dependent manner.
Statistical parametric mapping of the regional distribution and ontogenetic scaling of foot pressures during walking in Asian elephants (Elephas maximus)
Authors: Panagiotopoulou Olga , Pataky Todd C. , Hill Zoe , Hutchinson John R.
Published: April 2012

Foot pressure distributions during locomotion have causal links with the anatomical and structural configurations of the foot tissues and the mechanics of locomotion. Elephant feet have five toes bound in a flexible pad of fibrous tissue (digital cushion). Does this specialized foot design control peak foot pressures in such giant animals? And how does body size, such as during ontogenetic growth, influence foot pressures? We addressed these questions by studying foot pressure distributions in elephant feet and their correlation with body mass and centre of pressure trajectories, using statistical parametric mapping (SPM), a neuro-imaging technology. Our results show a positive correlation between body mass and peak pressures, with the highest pressures dominated by the distal ends of the lateral toes (digits 3, 4 and 5). We also demonstrate that pressure reduction in the elephant digital cushion is a complex interaction of its viscoelastic tissue structure and its centre of pressure trajectories, because there is a tendency to avoid rear ‘heel’ contact as an elephant grows. Using SPM, we present a complete map of pressure distributions in elephant feet during ontogeny by performing statistical analysis at the pixel level across the entire plantar/palmar surface. We hope that our study will build confidence in the potential clinical and scaling applications of mammalian foot pressures, given our findings in support of a link between regional peak pressures and pathogenesis in elephant feet.
Olfactory coding in five moth species from two families
Authors: Bisch-Knaden Sonja , Carlsson Mikael A. , Sugimoto Yuki , Schubert Marco , Mißbach Christine , Sachse Silke , Hansson Bill S.
Published: April 2012

The aim of the present study was to determine what impact phylogeny and life history might have on the coding of odours in the brain. Using three species of hawk moths (Sphingidae) and two species of owlet moths (Noctuidae), we visualized neural activity patterns in the antennal lobe, the first olfactory neuropil in insects, evoked by a set of ecologically relevant plant volatiles. Our results suggest that even between the two phylogenetically distant moth families, basic olfactory coding features are similar. But we also found different coding strategies in the moths’ antennal lobe; namely, more specific patterns for chemically similar odorants in the two noctuid species than in the three sphingid species tested. This difference demonstrates the impact of the phylogenetic distance between species from different families despite some parallel life history traits found in both families. Furthermore, pronounced differences in larval and adult diet among the sphingids did not translate into differences in the olfactory code; instead, the three species had almost identical coding patterns.
Experimental evaluation of the anti-attachment effect of microalgal mats on grazing activity of the sea urchin Strongylocentrotus nudus in oscillating flows
Authors: Kawamata Shigeru
Published: April 2012

Algal mats can hinder the adhesion of the tube feet of sea urchins. This leads to the hypothesis that the restriction of sea urchin feeding activity by wave action can potentially be enhanced by the presence of algal mats, which will facilitate the survival of kelp recruits at sites with wave action in urchin barrens. To evaluate the potential anti-attachment effect of algal mats on sea urchins, a laboratory tank experiment was performed on the movement of Strongylocentrotus nudus sea urchins and their grazing on juvenile kelp plants at the center of 30×30 cm flat test substrates with or without a thin-layer microalgal mat at four levels of oscillatory flow (maximum orbital velocity: 10, 20, 30 and 40 cm s–1). The grazing loss of kelp slightly increased with increasing velocity up to 30 cm s–1 in the absence of microalgal mats, while in contrast the loss substantially decreased at 30 cm s–1 in their presence. Sea urchins were dislodged more frequently at 20 cm s–1 or higher velocities in the presence of microalgal mats. Mats were frequently abraded by scraping by the adoral spines during urchin movement at high velocities (30 and 40 cm s–1) but were subject to no or only slight urchin grazing in most cases. The results indicate that the overall decrease in grazing loss of kelp within the microalgal mats was attributable to the anti-attachment effect on urchins during incursions rather than due to urchins grazing on the mats.
Control of d-octopine formation in scallop adductor muscle as revealed through thermodynamic studies of octopine dehydrogenase
Authors: van Os Nadine , Smits Sander H. J. , Schmitt Lutz , Grieshaber Manfred K.
Published: April 2012

Octopine dehydrogenase (OcDH) from the adductor muscle of the great scallop, Pecten maximus (Linné, 1758), catalyses the NADH-dependent condensation of l-arginine and pyruvate to d-octopine, NAD+ and water during escape swimming and subsequent recovery. During exercise, ATP is mainly provided by the transphosphorylation of phospho-l-arginine and to some extent by anaerobic glycolysis. NADH resulting from the glycolytic oxidation of 3-phosphoglyceraldehyde to 1,3-bisphosphoglycerate is reoxidized during d-octopine formation. In some scallops d-octopine starts to accumulate during prolonged, strong muscular work, whereas in other species d-octopine formation commences towards the end of swimming and continues to rise during subsequent recovery. The activity of OcDH is regulated by a mandatory, consecutive mode of substrate binding in the order NADH, l-arginine and pyruvate, as demonstrated by isothermal titration calorimetry. The first regulatory step in the forward reaction comprises the binding of NADH to OcDH with a dissociation constant Kd of 0.014±0.006 mmol l–1, which reflects a high affinity and tight association of the apoenzyme with the co-substrate. In the reverse direction, NAD+ binds first with a Kd of 0.20±0.004 mmol l–1 followed by d-octopine. The binary OcDH–NADH complex associates with l-arginine with a Kd of 5.5±0.05 mmol l–1. Only this ternary complex combines with pyruvate, with an estimated Kd of approximately 0.8 mmol l–1 as deduced from pyruvate concentrations determined in the muscle of exhausted scallops. At tissue concentrations of pyruvate between 0.5 and 1.2 mmol l–1 in the valve adductor muscle of fatigued P. maximus, binding of pyruvate to OcDH plays the most decisive role in initiating OcDH activity and, therefore, in controlling the onset of d-octopine formation.
Designing Ranking Systems for Hotels on Travel Search Engines by Mining User-Generated and Crowdsourced Content
Authors: Ghose Anindya , Ipeirotis Panagiotis G. , Li Beibei
Published: April 2012

User-generated content on social media platforms and product search engines is changing the way consumers shop for goods online. However, current product search engines fail to effectively leverage information created across diverse social media platforms. Moreover, current ranking algorithms in these product search engines tend to induce consumers to focus on one single product characteristic dimension (e.g., price, star rating). This approach largely ignores consumers' multidimensional preferences for products. In this paper, we propose to generate a ranking system that recommends products that provide, on average, the best value for the consumer's money. The key idea is that products that provide a higher surplus should be ranked higher on the screen in response to consumer queries. We use a unique data set of U.S. hotel reservations made over a three-month period through Travelocity, which we supplement with data from various social media sources using techniques from text mining, image classification, social geotagging, human annotations, and geomapping. We propose a random coefficient hybrid structural model, taking into consideration the two sources of consumer heterogeneity the different travel occasions and different hotel characteristics introduce. Based on the estimates from the model, we infer the economic impact of various location and service characteristics of hotels. We then propose a new hotel ranking system based on the average utility gain a consumer receives from staying in a particular hotel. By doing so, we can provide customers with the “best-value” hotels early on. Our user studies, using ranking comparisons from several thousand users, validate the superiority of our ranking system relative to existing systems on several travel search engines. On a broader note, this paper illustrates how social media can be mined and incorporated into a demand estimation model in order to generate a new ranking system in product search engines. We thus highlight the tight linkages between user behavior on social media and search engines. Our interdisciplinary approach provides several insights for using machine learning techniques in economics and marketing research.
Intraconnectivity and Interconnectivity: When Value Creation May Reduce Profits
Authors: He Tingting , Kuksov Dmitri , Narasimhan Chakravarthi
Published: April 2012

This paper analyses firms' decisions to provide connectivity to their customers. We distinguish between intraconnectivity—the ability of one firm's customers to connect to each other—and interconnectivity—the ability of one firm's customers to connect with another firm's customers. The profitability implications of allowing connectivity are not a straightforward consequence of the consumer value of connectivity, because connectivity affects not only the customer value but also the intensity of competition by creating or changing network externality. We find that if sales are driven by brand switching rather than by category expansion, a firm may find it optimal not to provide intraconnectivity even if providing it is not costly and may find it optimal to provide interconnectivity even at a cost exceeding the consumer value of connectivity. On the other hand, if category expansion is possible, providing intraconnectivity may be profitable. In this case, either the equilibrium intraconnectivity provision may be asymmetric or both firms may find it (individually) optimal to provide intraconnectivity. Under certain conditions in the latter case, the firms' choice of intraconnectivity is a prisoner's dilemma game.
DRESS Syndrome Associated with Deferasirox Treatment Recurrent Stress Cardiomyopathy Induced by Over-the-Counter Phenylephrine; Angular Cheilitis after Selective Serotonin Reuptake Inhibitor Treatment; Chemotherapy-Induced Spontaneous Orgasms; Liraglutide-Induced Acute Kidney Injury; Peripheral Edema Associated with Risperidone; Risk of Bleeding with Concurrent Use of Antibiotics and Warfarin
Authors: Sinister Joel
Published: April 2012

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) MEDWATCH program (800-FDA-1088). If you have reported an interesting, preventable ADR to MEDWATCH, please consider sharing the account with our readers. Write to Dr. Shuster at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-947-7797; fax: 215-914-1492; e-mail: joel.shuster@temple.edu ). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA's MEDWATCH program and Temple University School of Pharmacy. ISMP is an FDA MEDWATCH partner.
Drug Monographs: Crizotinib and Ruxolitinib
Authors: Chasick Ashley , Solimando Dominic A. , Waddell J. Aubrey
Published: April 2012

The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases.
The Pharmacy Practitioner's Guide to Publishing
Authors: Larochelle Joseph M. , King Allison R. , Tanas Majid , Day Kimberly , Marshall Helen M. , Patel Sony A , Tyler Ashley M.
Published: April 2012

Purpose

The purpose of this article is to encourage the pharmacy practitioner to submit scholarly work for publication by providing a guide to the process. As practitioners, pharmacists understand the importance of research and the dissemination of information. Although pharmacists are encouraged to do research, many are overwhelmed by the task. This article highlights the steps in the publication process and provides tips to encourage pharmacists to conduct research and publish their findings.

The first step in authoring is deciding on a subject matter that is worthy of publication. Many practitioners believe that placebo-controlled trials are the only worthy endeavors; however, other forms such as case reports and editorials are also essential. Inclusion of researchers with different professional backgrounds will provide a diverse team with vast perspectives. Once the project is identified and team assembled, institutional review board approval should be sought if the project includes human subjects. The target audience should be identified prior to the composition of the publication to allow for identification of the appropriate publication form. Manuscript preparation should be complete, concise, and informative. Special attention should be paid to the editing process. After submission to the particular venue, the peer-review process begins. After final publication, authors must decide the timeframe for updating the work.

Conclusion

Professional writing is a time-consuming and challenging activity, but it is essential to the advancement of science, the profession, and patient care. This guide hopes to encourage pharmacists to conduct research projects and publish the information regardless of whether it is a case report, a review article, a poster, or a placebo-controlled trial.
Approvals, Submission, and Important Labeling Changes for US Marketed Pharmaceuticals
Authors: Baker Danial E.
Published: April 2012

This monthly feature will help readers keep current on new drugs, new indications, dosage forms, and safety-related changes in labeling or use. Efforts have been made to ensure the accuracy of this information; however, if there are any questions, please let me know at bakerdan@wsu.edu .
Mind Maps: A Leadership Tool for Department and Practice Model Change
Authors: Enright Sharon M. , White Sara J.
Published: April 2012

The Director's Forum series is designed to guide pharmacy leaders in establishing patient-centered services in hospitals and health systems. This month's article is a primer in using the technique of mind mapping to clarify and simplify complex pharmacy department issues. Mind mapping uses a diagram to represent concepts, words, tasks, or other items related to a key central word or idea. Mind maps form, visualize, generate, categorize, and classify ideas and facilitate problem solving, writing, and decision making. Mind mapping helps to keep focus in an organization undergoing operational changes/interruptions. Mind maps may be used by pharmacy directors for strategic planning, project management, performance feedback, coaching or mentoring, teaching, presentations, systems analysis, priority setting, note taking, meeting preparation, and problem solving. Mind maps are a way pharmacy directors can solve problems, organize, and optimize their patient-centered pharmacy services. Articles in upcoming issues of the Director's Forum will demonstrate using mind mapping in fostering leadership development skills necessary to grow effective pharmacy practice models.
Analgosedation: A Paradigm Shift in Intensive Care Unit Sedation Practice
Authors: Devabhakthuni Sandeep , Armahizer Michael J , Dasta Joseph F , Kane-Gill Sandra L
Published: April 2012

Objective:

To critically evaluate the use of analgosedation in the management of agitation in critically ill mechanically ventilated patients.

Data Sources:

Literature was accessed through MEDLINE (1948-November 2011) and Cochrane Library (2011, issue 1) using the terms analgosedation, analgosedation, or analgesia-based sedation alone or in combination with intensive care unit or critically ill. Reference lists of related publications were also reviewed.

Study Selection and Data Extraction:

All articles published in English were evaluated. Randomized controlled trials examining critically ill mechanically ventilated patients older than 18 years were included.

Data Synthesis:

Limitations of current sedation practices include serious adverse drug events, prolonged mechanical ventilation time, and intensive care unit (ICU) length of stay. Studies have demonstrated that analgosedation, a strategy that manages patient pain and discomfort first, before providing sedative therapy, results in improved patient outcomes compared to standard sedative-hypnotic regimens. Nine randomized controlled trials comparing remifentanil-based analgosedation to other commonly used agents (fentanyl, midazolam, morphine, and propofol) for ICU sedation and 1 trial comparing morphine to daily sedation interruption with propofol or midazolam were reviewed. Remifentanil is an ideal agent for analgosedation due to its easy titratability and organ-in dependent metabolism. When compared to sedative-hypnotic regimens, remifentanil-based regimens were associated with shorter duration of mechanical ventilation, more rapid weaning from the ventilator, and shorter ICU length of stay. Compared to fentanyl-based regimens, remifentanil had similar efficacy with the exception of increased pain requirements upon remifentanil discontinuation. Analgosedation was well tolerated, with no significant differences in hemodynamic stability compared to sedative-hypnotic regimens.

Conclusions:

Analgosedation is an efficacious and well-tolerated approach to management of ICU sedation with improved patient outcomes compared to sedative-hypnotic approaches. Additional well-designed trials are warranted to clarify the role of analgosedation in the management of ICU sedation, including trials with nonopioid analgesics.
Necessary Intrusion or Criminalising the Innocent? An Exploration of Modern Criminal Vetting
Authors: Baldwin Chris
Published: April 2012

This article considers the processes of criminal vetting and outlines the legislative framework allowing such disclosures and subsequent judicial interpretation of that framework. The focus is on disclosure of non-conviction (so-called ‘soft’) materials on ‘enhanced’ certificates and subsequent challenges to those disclosures at judicial review. Key cases are analysed, including R (on the application of X) v Chief Constable of West Midlands Police (2004) and R (on the application of L) (FC) (Appellant) v Commissioner of Police of the Metropolis (Respondent) (2009). The proportionality test in R (L) is noted and its subsequent application in the recent decisions of R (on the application of C) v Chief Constable of Greater Manchester; Secretary of State for the Home Department (2011) and R (on the application of B) v Chief Constable of Derbyshire Constabulary (2011) is scrutinised. The article also highlights interference in Article 8 of the European Convention on Human Rights (right to privacy) and questions whether interference can be justified, and whether the present judicial focus on right of representations in such cases is misplaced.
Misconduct in a Public Office—Should it Still Be Prosecuted?
Authors: Parsons Simon
Published: April 2012

This article examines the common law crime of misconduct in a public office from its ancient origins, and considers the difficulties in defining the crime. These difficulties arise from the crime being very widely defined as it includes non-feasance, misfeasance, frauds and deceits, malfeasance and oppression. It is unclear whether these are separate categories or if they run into one another. It is also unclear if the crime is a conduct crime or whether material damage is required. It appears that the DPP requires material damage before a prosecution can take place. The article argues that as the elements of the crime are so uncertain, it should no longer be prosecuted especially in view of the availability of alternative statutory offences which could be charged instead of the misconduct crime. These statutory offences have the certainty which the misconduct crime lacks and they thus enable public officials to judge their future conduct.
HDAC1 Regulates Fear Extinction in Mice
Authors: Bahari-Javan Sanaz , Maddalena Andrea , Kerimoglu Cemil , Wittnam Jessica , Held Torsten , Bähr Mathias , Burkhardt Susanne , Delalle Ivanna , Kügler Sebastian , Fischer Andre , Sananbenesi Farahnaz
Published: April 2012

Histone acetylation has been implicated with the pathogenesis of neuropsychiatric disorders and targeting histone deacetylases (HDACs) using HDAC inhibitors was shown to be neuroprotective and to initiate neuroregenerative processes. However, little is known about the role of individual HDAC proteins during the pathogenesis of brain diseases. HDAC1 was found to be upregulated in patients suffering from neuropsychiatric diseases. Here, we show that virus-mediated overexpression of neuronal HDAC1 in the adult mouse hippocampus specifically affects the extinction of contextual fear memories, while other cognitive abilities were unaffected. In subsequent experiments we show that under physiological conditions, hippocampal HDAC1 is required for extinction learning via a mechanism that involves H3K9 deacetylation and subsequent trimethylation of target genes. In conclusion, our data show that hippocampal HDAC1 has a specific role in memory function.
Distinct Dendritic Spine and Nuclear Phases of Calcineurin Activation after Exposure to Amyloid-β Revealed by a Novel Fluorescence Resonance Energy Transfer Assay
Authors: Wu Hai-Yan , Hudry Eloise , Hashimoto Tadafumi , Uemura Kengo , Fan Zhan-Yun , Berezovska Oksana , Grosskreutz Cynthia L. , Bacskai Brian J. , Hyman Bradley T.
Published: April 2012

Calcineurin (CaN) activation is critically involved in the regulation of spine morphology in response to oligomeric amyloid-β (Aβ) as well as in synaptic plasticity in normal memory, but no existing techniques can monitor the spatiotemporal pattern of CaN activity. Here, we use a spectral fluorescence resonance energy transfer approach to monitor CaN activation dynamics in real time with subcellular resolution. When oligomeric Aβ derived from Tg2576 murine transgenic neurons or human AD brains were applied to wild-type murine primary cortical neurons, we observe a dynamic progression of CaN activation within minutes, first in dendritic spines, and then in the cytoplasm and, in hours, in the nucleus. CaN activation in spines leads to rapid but reversible morphological changes in spines and in postsynaptic proteins; longer exposure leads to NFAT (nuclear factor of activated T-cells) translocation to the nucleus and frank spine loss. These results provide a framework for understanding the role of calcineurin in synaptic alterations associated with AD pathogenesis.
Familial Frontotemporal Dementia-AssociatedPresenilin-1 c.548G>TMutation Causes Decreased mRNA Expression and Reduced Presenilin Function in Knock-In Mice
Authors: Watanabe Hirotaka , Xia Dan , Kanekiyo Takahisa , Kelleher Raymond J. , Shen Jie
Published: April 2012

Mutations in thepresenilin-1(PSEN1) gene are associated with familial Alzheimer's disease and frontotemporal dementia (FTD). Interestingly, neuropathological analysis of a Belgian FTD family carrying aPSEN1 c.548G>Tmutation confirmed neurodegeneration in the absence of amyloid plaques. To investigate the impact of thec.548G>Tmutation on presenilin-1 (PS1) functionin vivo, we introduced this mutation into the genomicPsen1locus. The resultingc.548G>Tknock-in (KI) mice are viable but express markedly lower levels ofPsen1mRNA and protein in the brain. This reduction is due to production of aberrantly spliced transcripts lacking either exon 6 or exons 6 and 7 and their subsequent degradation via non-sense-mediated decay (NMD); inhibition of NMD by cycloheximide treatment stabilized these transcripts and restored the level ofPsen1mRNA in KI/KI brains. Interestingly, the reduction ofPsen1mRNA expression and the degradation of aberrantPsen1splice products occur exclusively in the brain but not in other tissues. Consistent with decreasedPsen1expression, γ-secretase activity was strongly reduced in the cerebral cortex of KI mice, as measured byde novoγ-secretase-mediated cleavage of APP and Notch. Moreover, PS1 expressed fromPsen1cDNA carrying thec.548G>Tmutation displayed normal γ-secretase activity in cultured cells, indicating that the corresponding p.183G>V amino acid substitution does not affect γ-secretase activity. Finally,Psen1 c.548G>TKI/KI;Psen2−/−mice exhibited mild spatial memory deficits in the Morris water maze task. Together, our findings demonstrate that thec.548G>Tmutation results in a brain-specific loss of presenilin function due to decreasedPsen1mRNA expression.
Adaptor Protein LNK Is a Negative Regulator of Brain Neural Stem Cell Proliferation after Stroke
Authors: Ahlenius Henrik , Devaraju Karthikeyan , Monni Emanuela , Oki Koichi , Wattananit Somsak , Darsalia Vladimer , Iosif Robert E. , Torper Olof , Wood James C. , Braun Sebastian , Jagemann Lucas , Nuber Ulrike A. , Englund Elisabet , Jacobsen Sten-Eirik W. , Lindvall Olle , Kokaia Zaal
Published: April 2012

Ischemic stroke causes transient increase of neural stem and progenitor cell (NSPC) proliferation in the subventricular zone (SVZ), and migration of newly formed neuroblasts toward the damaged area where they mature to striatal neurons. The molecular mechanisms regulating this plastic response, probably involved in structural reorganization and functional recovery, are poorly understood. The adaptor protein LNK suppresses hematopoietic stem cell self-renewal, but its presence and role in the brain are poorly understood. Here we demonstrate that LNK is expressed in NSPCs in the adult mouse and human SVZ.Lnk−/−mice exhibited increased NSPC proliferation after stroke, but not in intact brain or following status epilepticus. Deletion ofLnkcaused increased NSPC proliferation while overexpression decreased mitotic activity of these cellsin vitro. We found thatLnkexpression after stroke increased in SVZ through the transcription factors STAT1/3. LNK attenuated insulin-like growth factor 1 signaling by inhibition of AKT phosphorylation, resulting in reduced NSPC proliferation. Our findings identify LNK as a stroke-specific, endogenous negative regulator of NSPC proliferation, and suggest that LNK signaling is a novel mechanism influencing plastic responses in postischemic brain.
Dynamical Properties of BOLD Activity from the Ventral Posteromedial Cortex Associated with Meditation and Attentional Skills
Authors: Pagnoni Giuseppe
Published: April 2012

Neuroimaging data suggest a link between the spontaneous production of thoughts during wakeful rest and slow fluctuations of activity in the default mode network (DMN), a set of brain regions with high basal metabolism and a major neural hub in the ventral posteromedial cortex (vPMC). Meta-awareness and regulation of mind-wandering are core cognitive components of most contemplative practices and to study their impact on DMN activity, we collected functional MRI (fMRI) data from a cohort of experienced Zen meditators and meditation-naive controls engaging in a basic attention-to-breathing protocol. We observed a significant group difference in the skewness of the fMRI BOLD signal from the vPMC, suggesting that the relative incidence of states of elevated vPMC activity was lower in meditators; furthermore, the same parameter was significantly correlated with performance on a rapid visual information processing (RVIP) test for sustained attention conducted outside the scanner. Finally, a functional connectivity analysis with the vPMC seed revealed a significant association of RVIP performance with the degree of temporal correlation between vPMC and the right temporoparietal junction (TPJ), a region strongly implicated in stimulus-triggered reorienting of attention. Together, these findings suggest that the vPMC BOLD signal skewness and the temporal relationship of vPMC and TPJ activities reflect the dynamic tension between mind-wandering, meta-awareness, and directed attention, and may represent a useful endophenotype for studying individual differences in attentional abilities and the impairment of the latter in specific clinical conditions.
Phosphorylation of Rpt6 Regulates Synaptic Strength in Hippocampal Neurons
Authors: Djakovic Stevan N. , Marquez-Lona Esther M. , Jakawich Sonya K. , Wright Rebecca , Chu Carissa , Sutton Michael A. , Patrick Gentry N.
Published: April 2012

It has become increasingly evident that protein degradation via the ubiquitin proteasome system plays a fundamental role in the development, maintenance and remodeling of synaptic connections in the CNS. We and others have recently described the activity-dependent regulation of proteasome activity and recruitment of proteasomes into spine compartments involving the phosphorylation of the 19S ATPase subunit, Rpt6, by the plasticity kinase Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) (Bingol and Schuman, 2006; Djakovic et al., 2009; Bingol et al, 2010). Here, we investigated the role of Rpt6 phosphorylation on proteasome function and synaptic strength. Utilizing a phospho-specific antibody we verified that Rpt6 is phosphorylated at Serine 120 (S120) by CaMKIIα. In addition, we found that Rpt6 is phosphorylated by CaMKIIα in an activity-dependent manner. Furthermore, we showed that a serine 120 to aspartic acid phospho-mimetic mutant of Rpt6 (S120D) increases its resistance to detergent extraction in rat hippocampal dendrites, indicating phosphorylated Rpt6 may promote the tethering of proteasomes to scaffolds and cytoskeletal components. Expression of Rpt6 S120D decreased miniature EPSC (mEPSC) amplitude, while expression of a phospho-dead mutant (S120A) increased mEPSC amplitude. Surprisingly, homeostatic scaling of mEPSC amplitude produced by chronic application of bicuculline or tetrodotoxin is both mimicked and occluded by altered Rpt6 phosphorylation. Together, these data suggest that CaMKII-dependent phosphorylation of Rpt6 at S120 may be an important regulatory mechanism for proteasome-dependent control of synaptic remodeling in slow homeostatic plasticity.
Schaffer-Specific Local Field Potentials Reflect Discrete Excitatory Events at Gamma Frequency That May Fire Postsynaptic Hippocampal CA1 Units
Authors: Fernández-Ruiz Antonio , Makarov Valeri A. , Benito Nuria , Herreras Oscar
Published: April 2012

Information processing and exchange between brain nuclei are made through spike series sent by individual neurons in highly irregular temporal patterns. Synchronization in cell assemblies, proposed as a network language for internal neural representations, still has little experimental support. We use a novel technique to extract pathway-specific local field potentials (LFPs) in the hippocampus to explore the ongoing temporal structure of a single presynaptic input, the CA3 Schaffer pathway, and its contribution to the spontaneous output of CA1 units in anesthetized rat. We found that Schaffer-specific LFPs are composed of a regular succession of pulse-like excitatory packages initiated by spontaneous clustered firing of CA3 pyramidal cells to which individual units contribute variably. A fraction of these packages readily induce firing of CA1 pyramidal cells and interneurons, the so-called Schaffer-driven spikes, revealing the presynaptic origin in the output code of single CA1 units. The output of 70% of CA1 pyramidal neurons contains up to 10% of such spikes. Our results suggest a hierarchical internal operation of the CA3 region based on sequential oscillatory activation of pyramidal cell assemblies whose activity partly gets in the output code at the next station. We conclude that CA1 output may directly reflect the activity of specific ensembles of CA3 neurons. Thus, the fine temporal structure of pathway-specific LFPs, as an accurate readout of the activity of a presynaptic population, is useful in searching for hidden presynaptic code in irregular spikes series of individual neurons and assemblies.
Transcript-Specific Associations of SLC12A5 (KCC2) in Human Prefrontal Cortex with Development, Schizophrenia, and Affective Disorders
Authors: Tao Ran , Li Chao , Newburn Erin N. , Ye Tianzhang , Lipska Barbara K. , Herman Mary M. , Weinberger Daniel R. , Kleinman Joel E. , Hyde Thomas M.
Published: April 2012

The neuron-specific K+-Cl−cotransporter SLC12A5, also known as KCC2, helps mediate the electrophysiological effects of GABA. The pattern of KCC2 expression during early brain development suggests that its upregulation drives the postsynaptic switch of GABA from excitation to inhibition. We previously found decreased expression of full-length KCC2 in the postmortem hippocampus of patients with schizophrenia, but not in the dorsolateral prefrontal cortex (DLPFC). Using PCR and rapid amplification of cDNA ends, we discovered several previously unrecognized alternative KCC2 transcripts in both human adult and fetal brain in addition to the previously identified full-length (NM_020708.3) and truncated (AK098371) transcripts. We measured the expression levels of four relatively abundant truncated splice variants, including three novel transcripts (ΔEXON6, EXON2B, and EXON6B) and one previously described transcript (AK098371), in a large human cohort of nonpsychiatric controls across the lifespan, and in patients with schizophrenia and affective disorders. In SH-SY5Y cell lines, these transcripts were translated into proteins and expressed at their predicted sizes. Expression of the EXON6B transcript is increased in the DLPFC of patients with schizophrenia (p= 0.03) but decreased in patients with major depression (p= 0.04). The expression of AK098371 is associated with aGAD1single nucleotide polymorphism (rs3749034) that previously has been associated with GAD67 expression and risk for schizophrenia. Our data confirm the developmental regulation of KCC2 expression, and provide evidence that KCC2 transcripts are differentially expressed in schizophrenia and affective disorders. Alternate transcripts from KCC2 may participate in the abnormal GABA signaling in the DLPFC associated with schizophrenia.
Comparative Anatomy of Marmoset and Mouse Cortex from Genomic Expression
Authors: Mashiko Hiromi , Yoshida Aya C. , Kikuchi Satomi S. , Niimi Kimie , Takahashi Eiki , Aruga Jun , Okano Hideyuki , Shimogori Tomomi
Published: April 2012

Advances in mouse neural circuit genetics, brain atlases, and behavioral assays provide a powerful system for modeling the genetic basis of cognition and psychiatric disease. However, a critical limitation of this approach is how to achieve concordance of mouse neurobiology with the ultimate goal of understanding the human brain. Previously, the common marmoset has shown promise as a genetic model system toward the linking of mouse and human studies. However, the advent of marmoset transgenic approaches will require an understanding of developmental principles in marmoset compared to mouse. In this study, we used gene expression analysis in marmoset brain to pose a series of fundamental questions on cortical development and evolution for direct comparison to existing mouse brain atlas expression data. Most genes showed reliable conservation of expression between marmoset and mouse. However, certain markers had strikingly divergent expression patterns. The lateral geniculate nucleus and pulvinar in the thalamus showed diversification of genetic organization between marmoset and mouse, suggesting they share some similarity. In contrast, gene expression patterns in early visual cortical areas showed marmoset-specific expression. In prefrontal cortex, some markers labeled architectonic areas and layers distinct between mouse and marmoset. Core hippocampus was conserved, while afferent areas showed divergence. Together, these results indicate that existing cortical areas are genetically conserved between marmoset and mouse, while differences in areal parcellation, afferent diversification, and layer complexity are associated with specific genes. Collectively, we propose that gene expression patterns in marmoset brain reveal important clues to the principles underlying the molecular evolution of cortical and cognitive expansion.
Pathways for Emotions and Attention Converge on the Thalamic Reticular Nucleus in Primates
Authors: Zikopoulos Basilis , Barbas Helen
Published: April 2012

How do emotional events readily capture our attention? To address this question we used neural tracers to label pathways linking areas involved in emotional and attentional processes in the primate brain (Macaca mulatta). We report that a novel pathway from the amygdala, the brain's emotional center, targets the inhibitory thalamic reticular nucleus (TRN), a key node in the brain's attentional network. The amygdalar pathway formed unusual synapses close to cell bodies of TRN neurons and had more large and efficient terminals than pathways from the orbitofrontal cortex and the thalamic mediodorsal nucleus, which similarly innervated extensive TRN sites. The robust amygdalar pathway provides a mechanism for rapid shifting of attention to emotional stimuli. Acting synergistically, pathways from the amygdala and orbitofrontal cortex provide a circuit for purposeful assessment of emotional stimuli. The different pathways to TRN suggest distinct mechanisms of attention to external and internal stimuli that may be differentially disrupted in anxiety and mood disorders and may be selectively targeted for therapeutic interventions.
A Model of Toxic Neuropathy inDrosophilaReveals a Role for MORN4 in Promoting Axonal Degeneration
Authors: Bhattacharya Martha R. C. , Gerdts Josiah , Naylor Sarah A. , Royse Emily X. , Ebstein Sarah Y. , Sasaki Yo , Milbrandt Jeffrey , DiAntonio Aaron
Published: April 2012

Axonal degeneration is a molecular self-destruction cascade initiated following traumatic, toxic, and metabolic insults. Its mechanism underlies a number of disorders including hereditary and diabetic neuropathies and the neurotoxic side effects of chemotherapy drugs. Molecules that promote axonal degeneration could represent potential targets for therapy. To identify such molecules, we designed a screening platform based on intoxication ofDrosophilalarvae with paclitaxel (taxol), a chemotherapeutic agent that causes neuropathy in cancer patients. InDrosophila, taxol treatment causes swelling, fragmentation, and loss of axons in larval peripheral nerves. This axonal loss is not due to apoptosis of neurons. Taxol-induced axonal degeneration inDrosophilashares molecular execution mechanisms with vertebrates, including inhibition by both NMNAT (nicotinamide mononucleotide adenylyltransferase) expression and loss ofwallenda/DLK (dual leucine zipper kinase). In a pilot RNAi-based screen we found that knockdown ofretinophilin(rtp), which encodes a MORN (membrane occupation and recognition nexus) repeat-containing protein, protects axons from degeneration in the presence of taxol. Loss-of-function mutants ofrtpreplicate this axonal protection. Knockdown ofrtpalso delays axonal degeneration in severed olfactory axons. We demonstrate that the mouse ortholog ofrtp, MORN4, promotes axonal degeneration in mouse sensory axons following axotomy, illustrating conservation of function. Hence, this new model can identify evolutionarily conserved genes that promote axonal degeneration, and so could identify candidate therapeutic targets for a wide-range of axonopathies.
Survival Motor Neuron Affects Plastin 3 Protein Levels Leading to Motor Defects
Authors: Hao Le T. , Wolman Marc , Granato Michael , Beattie Christine E.
Published: April 2012

The actin-binding protein plastin 3 (PLS3) has been identified as a modifier of the human motoneuron disease spinal muscular atrophy (SMA). SMA is caused by decreased levels of the survival motor neuron protein (SMN) and in its most severe form causes death in infants and young children. To understand the mechanism of PLS3 in SMA, we have analyzedpls3RNA and protein in zebrafishsmnmutants. We show that Pls3 protein levels are severely decreased insmn−/−mutants without a reduction inpls3mRNA levels. Moreover, we show that bothpls3mRNA and protein stability are unaffected when Smn is reduced. This indicates that SMN affects PLS3 protein production. We had previously shown that, insmnmutants, the presynaptic protein SV2 is decreased at neuromuscular junctions. Transgenically driving human PLS3 in motoneurons rescues the decrease in SV2 expression. To determine whether PLS3 could also rescue function, we performed behavioral analysis onsmnmutants and found that they had a significant decrease in spontaneous swimming and turning. Driving PLS3 transgenically in motoneurons rescued both of these defects. These data show that PLS3 protein levels are dependent on SMN and that PLS3 is able to rescue the neuromuscular defects and corresponding movement phenotypes caused by low levels of Smn suggesting that decreased PLS3 contributes to SMA motor phenotypes.
Interactions between Core and Matrix Thalamocortical Projections in Human Sleep Spindle Synchronization
Authors: Bonjean Maxime , Baker Tanya , Bazhenov Maxim , Cash Sydney , Halgren Eric , Sejnowski Terrence
Published: April 2012

Sleep spindles are bursts of 11–15 Hz that occur during non-rapid eye movement sleep. Spindles are highly synchronous across the scalp in the electroencephalogram (EEG) but have low spatial coherence and exhibit low correlation with the EEG when simultaneously measured in the magnetoencephalogram (MEG). We developed a computational model to explore the hypothesis that the spatial coherence spindles in the EEG is a consequence of diffuse matrix projections of the thalamus to layer 1 compared with the focal projections of the core pathway to layer 4 recorded in the MEG. Increasing the fanout of thalamocortical connectivity in the matrix pathway while keeping the core pathway fixed led to increased synchrony of the spindle activity in the superficial cortical layers in the model. In agreement with cortical recordings, the latency for spindles to spread from the core to the matrix was independent of the thalamocortical fanout but highly dependent on the probability of connections between cortical areas.
The Actin-Severing Protein Cofilin Is Downstream of Neuregulin Signaling and Is Essential For Schwann Cell Myelination
Authors: Sparrow Nicklaus , Manetti Maria Elisa , Bott Marga , Fabianac Tiffany , Petrilli Alejandra , Bates Margaret Longest , Bunge Mary Bartlett , Lambert Stephen , Fernandez-Valle Cristina
Published: April 2012

Myelination is a complex process requiring coordination of directional motility and an increase in glial cell size to generate a multilamellar myelin sheath. Regulation of actin dynamics during myelination is poorly understood. However, it is known that myelin thickness is related to the abundance of neuregulin-1 (NRG1) expressed on the axon surface. Here we identify cofilin1, an actin depolymerizing and severing protein, as a downstream target of NRG1 signaling in rat Schwann cells (SCs). In isolated SCs, NRG1 promotes dephosphorylation of cofilin1 and its upstream regulators, LIM kinase (LIMK) and Slingshot-1 phosphatase (SSH1), leading to cofilin1 activation and recruitment to the leading edge of the plasma membrane. These changes are associated with rapid membrane expansion yielding a 35–50% increase in SC size within 30 min. Cofilin1-deficient SCs increase phosphorylation of ErbB2, ERK, focal adhesion kinase, and paxillin in response to NRG1, but fail to increase in size possibly due to stabilization of unusually long focal adhesions. Cofilin1-deficient SCs cocultured with sensory neurons do not myelinate. Ultrastructural analysis reveals that they unsuccessfully segregate or engage axons and form only patchy basal lamina. After 48 h of coculturing with neurons, cofilin1-deficient SCs do not align or elongate on axons and often form adhesions with the underlying substrate. This study identifies cofilin1 and its upstream regulators, LIMK and SSH1, as end targets of a NRG1 signaling pathway and demonstrates that cofilin1 is necessary for dynamic changes in the cytoskeleton needed for axon engagement and myelination by SCs.