bluuebunny/crossref_metadata_2025 huggingface dataset:
Thinking Outside the Box
Authors: Gaither Sarah E. , Remedios Jessica D. , Sanchez Diana T. , Sommers Samuel R.
Published: January 2015

Rigid thinking is associated with less creativity, suggesting that priming a flexible mind-set should boost creative thought. In three studies, we investigate whether priming multiple social identities predicts more creativity in domains unrelated to social identity. Study 1 asked monoracial and multiracial participants to write about their racial identities before assessing creativity. Priming a multiracial’s racial identity led to greater creativity compared to a no-prime control. Priming a monoracial’s racial identity did not affect creativity. Study 2 showed that reminding monoracials that they, too, have multiple identities increased creativity. Study 3 replicated this effect and demonstrated that priming a multiracial identity for monoracials did not affect creativity. These results are the first to investigate the association between flexible identities and flexible thinking, highlighting the potential for identity versatility to predict cognitive differences between individuals who have singular versus multifaceted views of their social selves.
Role of neoadjuvant chemotherapy in muscle-invasive bladder cancer: Clinical and cost effectiveness
Authors: Goonewardene Sanchia S , Bahl Amit , Persad Raj
Published: January 2015

Background:

Bladder cancer is one of the most common cancers in the Western world, with associated significant mortality. Once proven to be muscle invasive, radical therapy is required.

Objective:

We reviewed the literature associated with clinical effectiveness of neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer.

Methods:

We conducted a systematic literature review of papers related to the search terms neoadjuvant chemotherapy, muscle invasive bladder cancer and clinical effectiveness; from 1984 through April 2014. We used the search terms of (neoadjuvant chemotherapy) AND (muscle invasive bladder cancer). We included primary research, but only included secondary research if it was a systematic review or meta-analyses. Papers outside this category were not included.

Results:

From the literature review, we found that the benefits of neoadjuvant chemotherapy for muscle-invasive bladder cancer are wide-ranging. This includes a greatly improved response rate, including complete response and improved survival rate. Potential disadvantages of NAC include less accurate staging, delays in curative surgery (risk is greater, if delay > 12 weeks) in non-responders and the well-known fact that non-responders will fare worse, later on.

Conclusions:

In conclusion, NAC followed by radical therapy is the gold standard for muscle-invasive bladder tumours, for patients whom are sufficiently fit; however, there are many unanswered questions. As yet, this intervention has not been examined by the National Institute for Health and Care Excellence.
Variation in Prices of Cardiovascular Drugs in Public and Private Pharmacies in Nepal
Authors: Mishra Shiva Raj , Kandel Nirajan , Subedi Narayan , Khanal Vishnu
Published: January 2015

Introduction:

Higher price of cardiovascular drugs is one of the reasons for high out-of-pocket expenditure in cardiovascular care. The objective of the study was to determine the price variation in commonly available cardiovascular drugs between public and private hospital pharmacies in Nepal.

Methods:

A cross-sectional survey was conducted in 3 public and 3 private pharmacies in tertiary-level hospitals in Nepal. The price was recorded for the list of drugs commonly available in those pharmacies. A total of 23 drugs were selected for data collection. The price was recorded based on the payment receipt and price reported by surrogate customers. We defined the price variation as the difference between price of cardiovascular drugs between public hospital and private pharmacy. The price variation was expressed as percentage.

Results:

Price of Amlodipine 5 mg was higher by 667% in private pharmacy nearby Tribhuvan University Teaching Hospital (TUTH) compared to that of TUTH pharmacy. Price of Enalapril 5 mg was higher by 14.47% in Manmohan Cardio Thoracic and Vascular Transplant Centre (MCVTC) compared to nearby private pharmacy. We observed that the price of cardiovascular drugs varied significantly between hospital and private retail pharmacies in TUTH ( P < .001) and MCVTC ( P < .001).

Conclusion:

For most of the cardiovascular drugs, the price in private retail pharmacies were significantly higher than in hospital pharmacies. Future steps should be taken to establish and run own pharmacies in hospitals which would reduce the cost of medicine and thereby, increase access to medicine.
Structure–mechanical property relationship in fused deposition modelling
Authors: Rezayat H. , Zhou W. , Siriruk A. , Penumadu D. , Babu S. S.
Published: January 2015

The relationship between the filament scale phenomena and the macroscopic properties of parts manufactured by fused deposition modelling (FDM) of thermoplastic polymers has been investigated using planar geometry dog bone samples, representing layer by layer lamina in an additively manufactured part. Finite element simulations of the response of the FDM part(s) at multiple length scales (filament to macro) are compared with full field strain data obtained experimentally for different raster angles and filament gaps. The strain field, strain energy density, and effective Young's modulus are evaluated. Principal strains resulting from the applied axial loading shifted from the inner rasters to the contours of the FDM planar sample at certain raster angles as the air gap increased, which significantly decreased the effective usage of the material leading to strain localization and premature part failure. The research presented provides a pathway to an effective multiscale approach to optimise the raster contour fill pattern.
Interleukin-13 is overexpressed in cutaneous T-cell lymphoma cells and regulates their proliferation
Authors: Geskin Larisa J. , Viragova Sara , Stolz Donna B. , Fuschiotti Patrizia
Published: January 2015

Key Points

IL-13 is an autocrine factor for CTCL. IL-13 and its receptors represent novel markers of CTCL malignancy and potential therapeutic targets for intervention.
Genetics of multiple myeloma: another heterogeneity level?
Authors: Corre Jill , Munshi Nikhil , Avet-Loiseau Hervé
Published: January 2015

Our knowledge of myeloma genetics remained limited and lagged behind many other hematologic malignancies because of the inherent difficulties in generating metaphases within the malignant plasma cell clone. With the development of molecular techniques (microarrays and next-generation sequencing), our understanding has been highly improved in the past 5 years. These studies have not only confirmed the prevalence of wide heterogeneity in myeloma at the molecular level, but has also provided a much clearer picture of the disease pathogenesis and progression. Whether these data will enable improvements in the therapeutic approach is still a matter of debate. The next improvement will come from detailed analyses of these molecular features to try to move from a treatment fitted to every patient to individualized therapies, taking into account the complexity of the chromosomal changes, the mutation spectrum, and subclonality evolution.
Astatine-211 conjugated to an anti-CD20 monoclonal antibody eradicates disseminated B-cell lymphoma in a mouse model
Authors: Green Damian J. , Shadman Mazyar , Jones Jon C. , Frayo Shani L. , Kenoyer Aimee L. , Hylarides Mark D. , Hamlin Donald K. , Wilbur D. Scott , Balkan Ethan R. , Lin Yukang , Miller Brian W. , Frost Sofia H. L. , Gopal Ajay K. , Orozco Johnnie J. , Gooley Theodore A. , Laird Kelly L. , Till Brian G. , Bäck Tom , Sandmaier Brenda M. , Pagel John M. , Press Oliver W.
Published: January 2015

Key Points

α-Emitting radionuclides have the potential to overcome treatment-resistant lymphoma cell clones that evade other forms of therapy. 211At-labeled anti-CD20 monoclonal antibody eradicates lymphoma in a mouse minimal residual disease model.
Efficiency of hydrogen peroxide in improving disinfection of ICU rooms
Authors: Blazejewski Caroline , Wallet Frédéric , Rouzé Anahita , Le Guern Rémi , Ponthieux Sylvie , Salleron Julia , Nseir Saad
Published: January 2015

Introduction

The primary objective of this study was to determine the efficiency of hydrogen peroxide (H2O2) techniques in disinfection of ICU rooms contaminated with multidrug-resistant organisms (MDRO) after patient discharge. Secondary objectives included comparison of the efficiency of a vaporizator (HPV, Bioquell®) and an aerosolizer using H2O2, and peracetic acid (aHPP, Anios®) in MDRO environmental disinfection, and assessment of toxicity of these techniques.

Methods

This prospective cross-over study was conducted in five medical and surgical ICUs located in one University hospital, during a 12-week period. Routine terminal cleaning was followed by H2O2 disinfection. A total of 24 environmental bacteriological samplings were collected per room, from eight frequently touched surfaces, at three time-points: after patient discharge (T0), after terminal cleaning (T1) and after H2O2 disinfection (T2).

Results

In total 182 rooms were studied, including 89 (49%) disinfected with aHPP and 93 (51%) with HPV. At T0, 15/182 (8%) rooms were contaminated with at least 1 MDRO (extended spectrum β–lactamase-producing Gram-negative bacilli 50%, imipenem resistant Acinetobacter baumannii 29%, methicillin-resistant Staphylococcus aureus 17%, and Pseudomonas aeruginosa resistant to ceftazidime or imipenem 4%). Routine terminal cleaning reduced environmental bacterial load (P <0.001) without efficiency on MDRO (15/182 (8%) rooms at T0 versus 11/182 (6%) at T1; P = 0.371). H2O2 technologies were efficient for environmental MDRO decontamination (6% of rooms contaminated with MDRO at T1 versus 0.5% at T2, P = 0.004). Patient characteristics were similar in aHPP and HPV groups. No significant difference was found between aHPP and HPV regarding the rate of rooms contaminated with MDRO at T2 (P = 0.313). 42% of room occupants were MDRO carriers. The highest rate of rooms contaminated with MDRO was found in rooms where patients stayed for a longer period of time, and where a patient with MDRO was hospitalized. The residual concentration of H2O2 appears to be higher using aHPP, compared with HPV.

Conclusions

H2O2 treatment is efficient in reducing MDRO contaminated rooms in the ICU. No significant difference was found between aHPP and HPV regarding their disinfection efficiency.
Pharmacokinetic variability and exposures of fluconazole, anidulafungin, and caspofungin in intensive care unit patients: Data from multinational Defining Antibiotic Levels in Intensive care unit (DALI) patients Study
Authors: Sinnollareddy Mahipal G , Roberts Jason A , Lipman Jeffrey , Akova Murat , Bassetti Matteo , De Waele Jan J , Kaukonen Kirsi-Maija , Koulenti Despoina , Martin Claude , Montravers Philippe , Rello Jordi , Rhodes Andrew , Starr Therese , Wallis Steven C , Dimopoulos George ,   on behalf of the DALI Study authors
Published: January 2015

Introduction

The objective of the study was to describe the pharmacokinetics (PK) of fluconazole, anidulafungin, and caspofungin in critically ill patients and to compare with previously published data. We also sought to determine whether contemporary fluconazole doses achieved PK/pharmacodynamic (PD; PK/PD) targets in this cohort of intensive care unit patients.

Methods

The Defining Antibiotic Levels in Intensive care unit patients (DALI) study was a prospective, multicenter point-prevalence PK study. Sixty-eight intensive care units across Europe participated. Inclusion criteria were met by critically ill patients administered fluconazole (n = 15), anidulafungin (n = 9), and caspofungin (n = 7). Three blood samples (peak, mid-dose, and trough) were collected for PK/PD analysis. PK analysis was performed by using a noncompartmental approach.

Results

The mean age, weight, and Acute Physiology and Chronic Health Evaluation (APACHE) II scores of the included patients were 58 years, 84 kg, and 22, respectively. Fluconazole, caspofungin, and anidulafungin showed large interindividual variability in this study. In patients receiving fluconazole, 33% did not attain the PK/PD target, ratio of free drug area under the concentration-time curve from 0 to 24 hours to minimum inhibitory concentration (fAUC0–24/MIC) ≥100. The fluconazole dose, described in milligrams per kilogram, was found to be significantly associated with achievement of fAUC0–24/MIC ≥100 (P = 0.0003).

Conclusions

Considerable interindividual variability was observed for fluconazole, anidulafungin, and caspofungin. A large proportion of the patients (33%) receiving fluconazole did not attain the PK/PD target, which might be related to inadequate dosing. For anidulafungin and caspofungin, dose optimization also appears necessary to minimize variability.
Avianbase: a community resource for bird genomics
Authors: Eöry Lél , Gilbert M Thomas P , Li Cai , Li Bo , Archibald Alan , Aken Bronwen L , Zhang Guojie , Jarvis Erich , Flicek Paul , Burt David W
Published: January 2015

Giving access to sequence and annotation data for genome assemblies is important because, while facilitating research, it places both assembly and annotation quality under scrutiny, resulting in improvements to both. Therefore we announce Avianbase, a resource for bird genomics, which provides access to data released by the Avian Phylogenomics Consortium.
What we can learn from animal models about cerebral multi-morbidity
Authors: Baker Siân , Götz Jürgen
Published: January 2015

Late-onset diseases such as Alzheimer’s disease, Parkinson’s disease, or frontotemporal lobar degeneration are considered to be protein-folding disorders, with the accumulation of protein deposits causing a gain-of-toxic function. Alzheimer’s disease is characterized by two histological hallmark lesions: amyloid-β-containing plaques and tau-containing neurofibrillary tangles. However, signature proteins, including α-synuclein, which are found in an aggregated fibrillar form in the Lewy bodies of Parkinson’s disease brains, are also frequently found in Alzheimer’s disease. This highlights the fact that, although specific aggregates form the basis for diagnosis, there is a high prevalence of clinical overlap between neuropathological lesions linked to different diseases, a finding known as cerebral co- or multi-morbidity. Furthermore, the proteins forming these lesions interact, and this interaction accelerates an ongoing degenerative process. Here, we review the contribution that transgenic animal models have made to a better mechanistic understanding of the causes and consequences of co- or multi-morbidity. We discuss selected vertebrate and invertebrate models as well as the insight gained from non-transgenic senescence-accelerated mouse-prone mice. This article is part of a series on ‘Cerebral multi-morbidity of the aging brain’.
Why do migrants remit? Testing hypotheses for the case of Morocco
Authors: Bouoiyour Jamal , Miftah Amal
Published: January 2015

We use Moroccan data to study the determinants of international migrants’ remittances, testing the altruistic and welfare hypotheses. In particular, we analyze and assess what motivates migrants to send remittances back home. Our results lend support to the altruistic hypothesis suggesting that remittances are sent to households with low levels of welfare. Furthermore, the decision to remit is intensely associated to individual characteristics such as migrant income, gender and age. Likewise, remittances may be viewed as loan repayment if the migration costs were borne by the remittance-receiving family.

JEL classification

F22, J61, D1, D91, O55.
19F MRI Probes with Tunable Switches and Highly Sensitive 19F MRI Nanoprobes
Authors: Kikuchi Kazuya
Published: January 2015

Magnetic resonance imaging (MRI) is an imaging modality adequate for in vivo studies. Therefore, many scientists are interested in the development of MRI probes capable of detecting enzyme activities in vivo. 19F MRI is useful for monitoring particular biosignals, cells, and target tissues, due to the absence of background signals in living organisms. Therefore, highly sensitive 19F MRI contrast agents are in great demand for their practical applications. However, we have faced the following challenges: (1) increasing the number of fluorine atoms decreases the solubility of the molecular probes, and (2) the restriction of the molecular mobility attenuates the 19F MRI signals. Herein, we developed novel multifunctional core–shell nanoparticles to solve these problems. They are composed of a core micelle filled with liquid perfluorocarbon and a robust silica shell. These core–shell nanoparticles have superior properties such as high sensitivity, surface-modifiability, biocompatibility, and sufficient in vivo stability. By the adequate surface modifications, gene expression in living cells and tumor tissue in living mice were successfully detected by 19F MRI.
A new species Larinodontes freidbergi sp. nov. (Coleoptera: Curculionidae: Lixinae) from India
Authors: Gültekin Levent , Friedman Ariel-Leib-Leonid
Published: January 2015

A new species in the genus Larinodontes Faust, 1898 is described from India, in addition to two previously known species. Diagnostic features of this species are: femoral tooth small, ventral tibial tooth undeveloped, protibial pre-mucro reduced, penis in dorsal view parallel sided at apical 2/3 and subapically with wide V-form angularly upwards. Description, diagnosis and illustrations of new species are presented.
A collaborative antimicrobial ward round can promote prudent antimicrobial practices in an emergency general surgical unit
Authors: Parry MG , Chan K , Ward R , Lal P
Published: January 2015

How to minimise the risk of healthcare-acquired infections.
Treasures from the Archives
Authors: Milovanovic Vida
Published: January 2015

Sinhalese Ola
Tiger Country
Authors: Whitaker Matthew
Published: January 2015

A play based on the life and times of a Bulletin regular
Redistributing prostheses – from Britain to Sri Lanka
Authors: Barnett-Vanes Ashton , Maruthappu Mahiben , Shalhoub Joseph , Homer-Vanniasinkam Shervanthi , Panagamuwa Bandara
Published: January 2015

How used British mobility devices are being turned into brand new limbs for Sri Lankans.
Good grief
Authors: Revill Jo
Published: January 2015

The suggestion that some deaths are better than others shows we still struggle to discuss this subject.
The future’s bright. The future’s orange?
Authors: Malone Paul
Published: January 2015

The potential for innovation is unlimited. But how do we harvest the fruit of these endeavours?
Behavioral and Circuit Basis of Sucrose Rejection byDrosophilaFemales in a Simple Decision-Making Task
Authors: Yang Chung-Hui , He Ruo , Stern Ulrich
Published: January 2015

Drosophila melanogasteregg-laying site selection offers a genetic model to study a simple form of value-based decision. We have previously shown thatDrosophilafemales consistently reject a sucrose-containing substrate and choose a plain (sucrose-free) substrate for egg laying in our sucrose versus plain decision assay. However, either substrate is accepted when it is the sole option. Here we describe the neural mechanism that underlies females' sucrose rejection in our sucrose versus plain assay. First, we demonstrate that females explored the sucrose substrate frequently before most egg-laying events, suggesting that they actively suppress laying eggs on the sucrose substrate as opposed to avoiding visits to it. Second, we show that activating a specific subset of DA neurons triggered a preference for laying eggs on the sucrose substrate over the plain one, suggesting that activating these DA neurons can increase the value of the sucrose substrate for egg laying. Third, we demonstrate that neither ablating nor inhibiting the mushroom body (MB), a knownDrosophilalearning and decision center, affected females' egg-laying preferences in our sucrose versus plain assay, suggesting that MB does not mediate this specific decision-making task. We propose that the value of a sucrose substrate— as an egg-laying option—can be adjusted by the activities of a specific DA circuit. Once the sucrose substrate is determined to be the lesser valued option, females execute their decision to reject this inferior substrate not by stopping their visits to it, but by actively suppressing their egg-laying motor program during their visits.
Visual Landmark Information Gains Control of the Head Direction Signal at the Lateral Mammillary Nuclei
Authors: Yoder Ryan M. , Peck James R. , Taube Jeffrey S.
Published: January 2015

The neural representation of directional heading is conveyed by head direction (HD) cells located in an ascending circuit that includes projections from the lateral mammillary nuclei (LMN) to the anterodorsal thalamus (ADN) to the postsubiculum (PoS). The PoS provides return projections to LMN and ADN and is responsible for the landmark control of HD cells in ADN. However, the functional role of the PoS projection to LMN has not been tested. The present study recorded HD cells from LMN after bilateral PoS lesions to determine whether the PoS provides landmark control to LMN HD cells. After the lesion and implantation of electrodes, HD cell activity was recorded while rats navigated within a cylindrical arena containing a single visual landmark or while they navigated between familiar and novel arenas of a dual-chamber apparatus. PoS lesions disrupted the landmark control of HD cells and also disrupted the stability of the preferred firing direction of the cells in darkness. Furthermore, PoS lesions impaired the stable HD cell representation maintained by path integration mechanisms when the rat walked between familiar and novel arenas. These results suggest that visual information first gains control of the HD cell signal in the LMN, presumably via the direct PoS → LMN projection. This visual landmark information then controls HD cells throughout the HD cell circuit.
Neural Cell Adhesion Molecule 2 Promotes the Formation of Filopodia and Neurite Branching by Inducing Submembrane Increases in Ca2+Levels
Authors: Sheng Lifu , Leshchyns'ka Iryna , Sytnyk Vladimir
Published: January 2015

Changes in expression of the neural cell adhesion molecule 2 (NCAM2) have been proposed to contribute to neurodevelopmental disorders in humans. The role of NCAM2 in neuronal differentiation remains, however, poorly understood. Using genetically encoded Ca2+reporters, we show that clustering of NCAM2 at the cell surface of mouse cortical neurons induces submembrane [Ca2+] spikes, which depend on the L-type voltage-dependent Ca2+channels (VDCCs) and require activation of the protein tyrosine kinase c-Src. We also demonstrate that clustering of NCAM2 induces L-type VDCC- and c-Src-dependent activation of CaMKII. NCAM2-dependent submembrane [Ca2+] spikes colocalize with the bases of filopodia. NCAM2 activation increases the density of filopodia along neurites and neurite branching and outgrowth in an L-type VDCC-, c-Src-, and CaMKII-dependent manner. Our results therefore indicate that NCAM2 promotes the formation of filopodia and neurite branching by inducing Ca2+influx and CaMKII activation. Changes in NCAM2 expression in Down syndrome and autistic patients may therefore contribute to abnormal neurite branching observed in these disorders.
The Effects of anAPOEPromoter Polymorphism on Human Cortical Morphology during Nondemented Aging
Authors: Chen Yaojing , Li Peng , Gu Bin , Liu Zhen , Li Xin , Evans Alan C. , Gong Gaolang , Zhang Zhanjun
Published: January 2015

Apolipoprotein E (APOE) is the best-known susceptibility gene for AD. It has been well demonstrated that the ε4 allele of theAPOEgene can affect brain structure/function in nondemented individuals; however, other polymorphisms in theAPOEgene have been largely overlooked when assessing the effects ofAPOEon the neural system. Rs405509 is a newly recognized AD-related polymorphism located in theAPOEpromoter region that can regulate the transcriptional activity of theAPOEgene. To date, it remains unknown whether and how thisAPOEpromoter polymorphism affects the human brain in aging. Here, for the first time, we investigate the effects of the rs405509 genotype (T/T vs G-allele) on human cortical morphology using a large cohort of nondemented elderly subjects (120 subjects in total; aged 52– 81 years). High-resolution structural MRI was performed; cortical thickness and surface area were analyzed separately. Intriguingly, nondemented carriers of the rs405509 T/T genotype showed an accelerated age-related reduction of thickness in the left parahippocampal gyrus compared with the G-allele carriers. Furthermore, the cortical thickness covariance between the left parahippocampal gyrus and left medial cortex, including the left medial superior frontal gyrus, supplementary motor area, and paracentral lobule, was modulated by the interaction of the rs405509 genotype and age. These novel findings suggest an important role for theAPOEpromoter polymorphism in the human brain and also provide valuable insights into how the rs405509 genotype shapes the neural system to modulate the risk of developing AD.
Bax Regulates Neuronal Ca2+Homeostasis
Authors: D'Orsi Beatrice , Kilbride Seán M. , Chen Gang , Perez Alvarez Sergio , Bonner Helena P. , Pfeiffer Shona , Plesnila Nikolaus , Engel Tobias , Henshall David C. , Düssmann Heiko , Prehn Jochen H.M.
Published: January 2015

Excessive Ca2+entry during glutamate receptor overactivation (“excitotoxicity”) induces acute or delayed neuronal death. We report here that deficiency inbaxexerted broad neuroprotection against excitotoxic injury and oxygen/glucose deprivation in mouse neocortical neuron cultures and reduced infarct size, necrotic injury, and cerebral edema formation after middle cerebral artery occlusion in mice. Neuronal Ca2+and mitochondrial membrane potential (Δψm) analysis during excitotoxic injury revealed thatbax-deficient neurons showed significantly reduced Ca2+transients during the NMDA excitation period and did not exhibit the deregulation of Δψmthat was observed in their wild-type (WT) counterparts. Reintroduction ofbaxor abaxmutant incapable of proapoptotic oligomerization equally restored neuronal Ca2+dynamics during NMDA excitation, suggesting that Bax controlled Ca2+signaling independently of its role in apoptosis execution. Quantitative confocal imaging of intracellular ATP or mitochondrial Ca2+levels using FRET-based sensors indicated that the effects ofbaxdeficiency on Ca2+handling were not due to enhanced cellular bioenergetics or increased Ca2+uptake into mitochondria. We also observed that mitochondria isolated from WT orbax-deficient cells similarly underwent Ca2+-induced permeability transition. However, when Ca2+uptake into the sarco/endoplasmic reticulum was blocked with the Ca2+-ATPase inhibitor thapsigargin,bax-deficient neurons showed strongly elevated cytosolic Ca2+levels during NMDA excitation, suggesting that the ability of Bax to support dynamic ER Ca2+handling is critical for cell death signaling during periods of neuronal overexcitation.
Designer Receptors Enhance Memory in a Mouse Model of Down Syndrome
Authors: Fortress Ashley M. , Hamlett Eric D. , Vazey Elena M. , Aston-Jones Gary , Cass Wayne A. , Boger Heather A. , Granholm Ann-Charlotte E.
Published: January 2015

Designer receptors exclusively activated by designer drugs (DREADDs) are novel and powerful tools to investigate discrete neuronal populations in the brain. We have used DREADDs to stimulate degenerating neurons in a Down syndrome (DS) model, Ts65Dn mice. Individuals with DS develop Alzheimer's disease (AD) neuropathology and have elevated risk for dementia starting in their 30s and 40s. Individuals with DS often exhibit working memory deficits coupled with degeneration of the locus coeruleus (LC) norepinephrine (NE) neurons. It is thought that LC degeneration precedes other AD-related neuronal loss, and LC noradrenergic integrity is important for executive function, working memory, and attention. Previous studies have shown that LC-enhancing drugs can slow the progression of AD pathology, including amyloid aggregation, oxidative stress, and inflammation. We have shown that LC degeneration in Ts65Dn mice leads to exaggerated memory loss and neuronal degeneration. We used a DREADD, hM3Dq, administered via adeno-associated virus into the LC under a synthetic promoter, PRSx8, to selectively stimulate LC neurons by exogenous administration of the inert DREADD ligand clozapine-N-oxide. DREADD stimulation of LC-NE enhanced performance in a novel object recognition task and reduced hyperactivity in Ts65Dn mice, without significant behavioral effects in controls. To confirm that the noradrenergic transmitter system was responsible for the enhanced memory function, the NE prodrugl-threo-dihydroxyphenylserine was administered in Ts65Dn and normosomic littermate control mice, and produced similar behavioral results. Thus, NE stimulation may prevent memory loss in Ts65Dn mice, and may hold promise for treatment in individuals with DS and dementia.
The Role of Telomerase Protein TERT in Alzheimer's Disease and in Tau-Related PathologyIn Vitro
Authors: Spilsbury Alison , Miwa Satomi , Attems Johannes , Saretzki Gabriele
Published: January 2015

The telomerase reverse transcriptase protein TERT has recently been demonstrated to have a variety of functions bothin vitroandin vivo, which are distinct from its canonical role in telomere extension. In different cellular systems, TERT protein has been shown to be protective through its interaction with mitochondria. TERT has previously been found in rodent neurons, and we hypothesize that it might have a protective function in adult human brain. Here, we investigated the expression of TERT at different stages of Alzheimer's disease pathology (Braak Stages I-VI)in situand the ability of TERT to protect against oxidative damage in anin vitromodel of tau pathology. Our data reveal that TERT is expressedin vitroin mouse neurons and microglia, andin vivoin the cytoplasm of mature human hippocampal neurons and activated microglia, but is absent from astrocytes. Intriguingly, hippocampal neurons expressing TERT did not contain hyperphosphorylated tau. Vice versa, neurons that expressed high levels of pathological tau did not appear to express TERT protein. TERT protein colocalized with mitochondria in the hippocampus of Alzheimer's disease brains (Braak Stage VI), as well as in cultured neurons under conditions of oxidative stress. Ourin vitrodata suggest that the absence of TERT increases ROS generation and oxidative damage in neurons induced by pathological tau. Together, our findings suggest that TERT protein persists in neurons of the adult human brain, where it may have a protective role against tau pathology.
Dynamic Modulation of the Action Observation Network by Movement Familiarity
Authors: Gardner Tom , Goulden Nia , Cross Emily S.
Published: January 2015

When watching another person's actions, a network of sensorimotor brain regions, collectively termed the action observation network (AON), is engaged. Previous research suggests that the AON is more responsive when watching familiar compared with unfamiliar actions. However, most research into AON function is premised on comparisons of AON engagement during different types of task using univariate, magnitude-based approaches. To better understand the relationship between action familiarity and AON engagement, here we examine how observed movement familiarity modulates AON activity in humans using dynamic causal modeling, a type of effective connectivity analysis. Twenty-one subjects underwent fMRI scanning while viewing whole-body dance movements that varied in terms of their familiarity. Participants' task was to either predict the next posture the dancer's body would assume or to respond to a non–action-related attentional control question. To assess individuals' familiarity with each movement, participants rated each video on a measure of visual familiarity after being scanned. Parametric analyses showed more activity in left middle temporal gyrus, inferior parietal lobule, and inferior frontal gyrus as videos were rated as increasingly familiar. These clusters of activity formed the regions of interest for dynamic causal modeling analyses, which revealed attenuation of effective connectivity bidirectionally between parietal and temporal AON nodes when participants observed videos they rated as increasingly familiar. As such, the findings provide partial support for a predictive coding model of the AON, as well as illuminate how action familiarity manipulations can be used to explore simulation-based accounts of action understanding.
Daily Marijuana Use Is Not Associated with Brain Morphometric Measures in Adolescents or Adults
Authors: Weiland Barbara J. , Thayer Rachel E. , Depue Brendan E. , Sabbineni Amithrupa , Bryan Angela D. , Hutchison Kent E.
Published: January 2015

Recent research has suggested that marijuana use is associated with volumetric and shape differences in subcortical structures, including the nucleus accumbens and amygdala, in a dose-dependent fashion. Replication of such results in well controlled studies is essential to clarify the effects of marijuana. To that end, this retrospective study examined brain morphology in a sample of adult daily marijuana users (n= 29) versus nonusers (n= 29) and a sample of adolescent daily users (n= 50) versus nonusers (n= 50). Groups were matched on a critical confounding variable, alcohol use, to a far greater degree than in previously published studies. We acquired high-resolution MRI scans, and investigated group differences in gray matter using voxel-based morphometry, surface-based morphometry, and shape analysis in structures suggested to be associated with marijuana use, as follows: the nucleus accumbens, amygdala, hippocampus, and cerebellum. No statistically significant differences were found between daily users and nonusers on volume or shape in the regions of interest. Effect sizes suggest that the failure to find differences was not due to a lack of statistical power, but rather was due to the lack of even a modest effect. In sum, the results indicate that, when carefully controlling for alcohol use, gender, age, and other variables, there is no association between marijuana use and standard volumetric or shape measurements of subcortical structures.
Creatine Supplementation Enhances Corticomotor Excitability and Cognitive Performance during Oxygen Deprivation
Authors: Turner Clare E. , Byblow Winston D. , Gant Nicholas
Published: January 2015

Impairment or interruption of oxygen supply compromises brain function and plays a role in neurological and neurodegenerative conditions. Creatine is a naturally occurring compound involved in the buffering, transport, and regulation of cellular energy, with the potential to replenish cellular adenosine triphosphate without oxygen. Creatine is also neuroprotectivein vitroagainst anoxic/hypoxic damage. Dietary creatine supplementation has been associated with improved symptoms in neurological disorders defined by impaired neural energy provision. Here we investigate, for the first time in humans, the utility of creatine as a dietary supplement to protect against energetic insult. The aim of this study was to assess the influence of oral creatine supplementation on the neurophysiological and neuropsychological function of healthy young adults during acute oxygen deprivation. Fifteen healthy adults were supplemented with creatine and placebo treatments for 7 d, which increased brain creatine on average by 9.2%. A hypoxic gas mixture (10% oxygen) was administered for 90 min, causing global oxygen deficit and impairing a range of neuropsychological processes. Hypoxia-induced decrements in cognitive performance, specifically attentional capacity, were restored when participants were creatine supplemented, and corticomotor excitability increased. A neuromodulatory effect of creatine via increased energy availability is presumed to be a contributing factor of the restoration, perhaps by supporting the maintenance of appropriate neuronal membrane potentials. Dietary creatine monohydrate supplementation augments neural creatine, increases corticomotor excitability, and prevents the decline in attention that occurs during severe oxygen deficit. This is the first demonstration of creatine's utility as a neuroprotective supplement when cellular energy provision is compromised.
Neural Alpha Dynamics in Younger and Older Listeners Reflect Acoustic Challenges and Predictive Benefits
Authors: Wöstmann Malte , Herrmann Björn , Wilsch Anna , Obleser Jonas
Published: January 2015

Speech comprehension in multitalker situations is a notorious real-life challenge, particularly for older listeners. Younger listeners exploit stimulus-inherent acoustic detail, but are they also actively predicting upcoming information? And further, how do older listeners deal with acoustic and predictive information? To understand the neural dynamics of listening difficulties and according listening strategies, we contrasted neural responses in the alpha-band (∼10 Hz) in younger (20–30 years,n= 18) and healthy older (60–70 years,n= 20) participants under changing task demands in a two-talker paradigm. Electroencephalograms were recorded while humans listened to two spoken digits against a distracting talker and decided whether the second digit was smaller or larger. Acoustic detail (temporal fine structure) and predictiveness (the degree to which the first digit predicted the second) varied orthogonally. Alpha power at widespread scalp sites decreased with increasing acoustic detail (during target digit presentation) but also with increasing predictiveness (in-between target digits). For older compared with younger listeners, acoustic detail had a stronger impact on task performance and alpha power modulation. This suggests that alpha dynamics plays an important role in the changes in listening behavior that occur with age. Last, alpha power variations resulting from stimulus manipulations (of acoustic detail and predictiveness) as well as task-independent overall alpha power were related to subjective listening effort. The present data show that alpha dynamics is a promising neural marker of individual difficulties as well as age-related changes in sensation, perception, and comprehension in complex communication situations.
Rescue of Impaired Long-Term Facilitation at Sensorimotor Synapses ofAplysiafollowing siRNA Knockdown of CREB1
Authors: Zhou Lian , Zhang Yili , Liu Rong-Yu , Smolen Paul , Cleary Leonard J. , Byrne John H.
Published: January 2015

Memory impairment is often associated with disrupted regulation of gene induction. For example, deficits in cAMP response element-binding protein (CREB) binding protein (CBP; an essential cofactor for activation of transcription by CREB) impair long-term synaptic plasticity and memory. Previously, we showed that small interfering RNA (siRNA)-induced knockdown of CBP in individual sensory neurons significantly reduced levels of CBP and impaired 5-HT-induced long-term facilitation (LTF) in sensorimotor cocultures fromAplysia. Moreover, computational simulations of the biochemical cascades underlying LTF successfully predicted training protocols that restored LTF following CBP knockdown. We examined whether simulations could also predict a training protocol that restores LTF impaired by siRNA-induced knockdown of the transcription factor CREB1. Simulations based on a previously described model predicted rescue protocols that were specific to CREB1 knockdown. Empirical studies demonstrated that one of these rescue protocols partially restored impaired LTF. In addition, the effectiveness of the rescue protocol was enhanced by pretreatment with rolipram, a selective cAMP phosphodiesterase inhibitor. These results provide further evidence that computational methods can help rescue disruptions in signaling cascades underlying memory formation. Moreover, the study demonstrates that the effectiveness of computationally designed training protocols can be enhanced with complementary pharmacological approaches.
A Distinct Subtype of Dopaminergic Interneuron Displays Inverted Structural Plasticity at the Axon Initial Segment
Authors: Chand Annisa N. , Galliano Elisa , Chesters Robert A. , Grubb Matthew S.
Published: January 2015

The axon initial segment (AIS) is a specialized structure near the start of the axon that is a site of neuronal plasticity. Changes in activity levelsin vitroandin vivocan produce structural AIS changes in excitatory cells that have been linked to alterations in excitability, but these effects have never been described in inhibitory interneurons. In the mammalian olfactory bulb (OB), dopaminergic interneurons are particularly plastic, undergoing constitutive turnover throughout life and regulating tyrosine hydroxylase expression in an activity-dependent manner. Here we used dissociated cultures of rat and mouse OB to show that a subset of bulbar dopaminergic neurons possess an AIS and that these AIS-positive cells are morphologically and functionally distinct from their AIS-negative counterparts. Under baseline conditions, OB dopaminergic AISs were short and located distally along the axon but, in response to chronic 24 h depolarization, lengthened and relocated proximally toward the soma. These activity-dependent changes were in the opposite direction to both those we saw in non-GABAergic OB neurons and those reported previously for excitatory cell types. Inverted AIS plasticity in OB dopaminergic cells was bidirectional, involved all major components of the structure, was dependent on the activity of L-type CaV1 calcium channels but not on the activity of the calcium-activated phosphatase calcineurin, and was opposed by the actions of cyclin-dependent kinase 5. Such distinct forms of AIS plasticity in inhibitory interneurons and excitatory projection neurons may allow considerable flexibility when neuronal networks must adapt to perturbations in their ongoing activity.
Seeing Is Not Feeling: Posterior Parietal But Not Somatosensory Cortex Engagement During Touch Observation
Authors: Chan Annie W.-Y. , Baker Chris I.
Published: January 2015

Observing touch has been reported to elicit activation in human primary and secondary somatosensory cortices and is suggested to underlie our ability to interpret other's behavior and potentially empathy. However, despite these reports, there are a large number of inconsistencies in terms of the precise topography of activation, the extent of hemispheric lateralization, and what aspects of the stimulus are necessary to drive responses. To address these issues, we investigated the localization and functional properties of regions responsive to observed touch in a large group of participants (n= 40). Surprisingly, even with a lenient contrast of hand brushing versus brushing alone, we did not find any selective activation for observed touch in the hand regions of somatosensory cortex but rather in superior and inferior portions of neighboring posterior parietal cortex, predominantly in the left hemisphere. These regions in the posterior parietal cortex required the presence of both brush and hand to elicit strong responses and showed some selectivity for the form of the object or agent of touch. Furthermore, the inferior parietal region showed nonspecific tactile and motor responses, suggesting some similarity to area PFG in the monkey. Collectively, our findings challenge the automatic engagement of somatosensory cortex when observing touch, suggest mislocalization in previous studies, and instead highlight the role of posterior parietal cortex.
Listening to the Brainstem: Musicianship Enhances Intelligibility of Subcortical Representations for Speech
Authors: Weiss Michael W. , Bidelman Gavin M.
Published: January 2015

Auditory experiences including musicianship and bilingualism have been shown to enhance subcortical speech encoding operating below conscious awareness. Yet, the behavioral consequence of such enhanced subcortical auditory processing remains undetermined. Exploiting their remarkable fidelity, we examined the intelligibility of auditory playbacks (i.e., “sonifications”) of brainstem potentials recorded in human listeners. We found naive listeners' behavioral classification of sonifications was faster and more categorical when evaluating brain responses recorded in individuals with extensive musical training versus those recorded in nonmusicians. These results reveal stronger behaviorally relevant speech cues in musicians' neural representations and demonstrate causal evidence that superior subcortical processing creates a more comprehensible speech signal (i.e., to naive listeners). We infer that neural sonifications of speech-evoked brainstem responses could be used in the early detection of speech–language impairments due to neurodegenerative disorders, or in objectively measuring individual differences in speech reception solely by listening to individuals' brain activity.
Hyperexcitability of Rat Thalamocortical Networks after Exposure to General Anesthesia during Brain Development
Authors: DiGruccio Michael R. , Joksimovic Srdjan , Joksovic Pavle M. , Lunardi Nadia , Salajegheh Reza , Jevtovic-Todorovic Vesna , Beenhakker Mark P. , Goodkin Howard P. , Todorovic Slobodan M.
Published: January 2015

Prevailing literature supports the idea that common general anesthetics (GAs) cause long-term cognitive changes and neurodegeneration in the developing mammalian brain, especially in the thalamus. However, the possible role of GAs in modifying ion channels that control neuronal excitability has not been taken into consideration. Here we show that rats exposed to GAs at postnatal day 7 display a lasting reduction in inhibitory synaptic transmission, an increase in excitatory synaptic transmission, and concomitant increase in the amplitude of T-type calcium currents (T-currents) in neurons of the nucleus reticularis thalami (nRT). Collectively, this plasticity of ionic currents leads to increased action potential firingin vitroand increased strength of pharmacologically induced spike and wave dischargesin vivo. Selective blockade of T-currents reversed neuronal hyperexcitabilityin vitroandin vivo. We conclude that drugs that regulate thalamic excitability may improve the safety of GAs used during early brain development.