bluuebunny/crossref_metadata_2025 huggingface dataset:
Vilazodone for the Treatment of Major Depressive Disorder
Authors: Iranikhah Maryam , Wensel Terri M. , Thomason Angela R.
Published: October 2012

Major depressive disorder (MDD) affects 121 million people globally and is one of the leading causes of functional disability worldwide. As a recurrent disorder, MDD is associated with significant morbidity and functional disability as well as high direct and indirect costs to the health care system. Although several drug therapies are available for treating MDD, many patients do not achieve a sustained remission. Vilazodone was approved by the United States Food and Drug Administration in 2011 and has a distinctive pharmacology profile, as the drug is a selective serotonin reuptake inhibitor and serotonin 5‐HT1A receptor partial agonist. In two 8‐week, double‐blind, placebo‐controlled trials, vilazodone's overall rate of response was similar to other antidepressants for the treatment of MDD. Compared with placebo, remission rates were not significantly different in one trial and were not reported in the second trial. Vilazodone was generally well tolerated, with nausea and diarrhea being the most frequent adverse events reported. Postmarketing studies and further active comparative studies will provide additional insight to the potential benefits and safety of this novel drug.
Psychological and Physical Impact of Anabolic‐Androgenic Steroid Dependence
Authors: Ip Eric J. , Lu Debbie H. , Barnett Mitchell J. , Tenerowicz Michael J. , Vo Justin C. , Perry Paul J.
Published: October 2012

Study Objective

To contrast the characteristics of two groups of anabolic‐androgenic steroid (AAS) users—those with versus those without AAS dependence.

Design

Subanalysis of data from the Anabolic 500, a cross‐sectional survey.

Participants

One hundred twelve male AAS‐dependent users and 367 AAS‐nondependent users who completed an online survey between February 19 and June 30, 2009.

Measurements and Main Results

Respondents were recruited from the Internet discussion boards of 38 fitness, bodybuilding, weightlifting, and steroid Web sites. The respondents provided online informed consent and completed the Anabolic 500, a 99‐item Web‐based survey. Self‐reported data included demographics, exercise patterns, use of AAS and other performance‐enhancing agents, adverse effects of AAS use, behavior consistent with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM‐IV‐TR) criteria for AAS dependence, history of illicit drug and alcohol use, history of sexual or physical abuse, and psychiatric conditions diagnosed according to the DSM‐IV‐TR. Behavior consistent with AAS dependence was identified in 23.4% of the survey participants. These AAS‐dependent users were more excessive in their AAS use (e.g., higher doses, higher quantity of agents, longer duration of use), more likely to report a history of illicit heroin use in the last 12 months (5.4% vs 1.9%, p=0.049), and more likely to report a diagnosis of an anxiety disorder (16.1 vs 8.4%, p=0.020) or major depressive disorder (15.2% vs 7.4%, p=0.012) than AAS‐nondependent users.

Conclusion

Data from the Anabolic 500 survey showed that almost one quarter of AAS users were dependent on these drugs. These AAS‐dependent users had a higher rate of heroin use as well as anxiety and major depressive disorders compared with AAS‐nondependent users. These findings can help clinicians and researchers better understand and address the potential illicit drug use and psychiatric comorbidities that may be present among AAS‐dependent users.
Cost of Invasive Fungal Infections in the Era of New Diagnostics and Expanded Treatment Options
Authors: Ashley Elizabeth Dodds , Drew Richard , Johnson Melissa , Danna Robert , Dabrowski Dominika , Walker Valery , Prasad Manishi , Alexander Barbara , Papadopoulos George , Perfect John
Published: October 2012

Study Objective

To determine the true institutional cost of treating invasive fungal infections in light of recent advances in diagnostic techniques and antifungal therapies for both treatment and prophylaxis of these infections.

Design

Economic analysis.

Setting

Academic medical center.

Patients

A total of 200 patients discharged from the hospital during 2004–2005 with a diagnosis of proven, probable, or possible aspergillosis, cryptococcosis, invasive candidiasis, or zygomycosis (cases). Patients were matched in a 1:1 fashion with patients having similar underlying disease states but no invasive fungal infections (controls).

Measurements and Main Results

Data on demographic and clinical characteristics were collected from patients' medical records. In addition, information concerning each patient's hospitalization was recorded. Resource utilization data for a patient's entire hospitalization were collected from the hospital's charge databases and converted to costs. These data were compared between the cases and the controls. After adjusting for race‐ethnicity, sex, age, and comorbid illnesses, mean total hospital cost for cases was $32,196 more than for controls (p<0.0001). Nonpharmacy costs accounted for the majority (63%) of this difference, and an additional $3996 was attributed to systemic antifungal drugs. The mean length of hospital stay was longer for cases than controls (25.8 vs 18.4 days).

Conclusion

Treatment of patients with invasive fungal infections was associated with a significantly higher inpatient hospital cost compared with controls. However, due to new diagnostic techniques and effective antifungal therapy, the relative cost of these infections appears to be at least stable compared with the previous decade. These findings can help assess the utility of cost‐avoidance strategies such as antifungal prophylaxis and application of appropriate treatment.
Pay satisfaction and work–family conflict across time
Authors: Bhave Devasheesh P. , Kramer Amit , Glomb Theresa M.
Published: October 2012

On the basis of justice and exchange theories, the authors propose that employees offset their levels of work–family conflict (WFC) with their levels of pay satisfaction. Results based on two waves of data indicate that pay satisfaction has a negative relationship with WFC after controlling for actual pay and other work‐related and family‐related variables. Analysis of pay satisfaction dimensions reveals that satisfaction with benefits and pay structure are negatively related to WFC, whereas satisfaction with pay level and pay raise are not. Number of dependents and level of education moderate the relationship between pay satisfaction and WFC; specifically, having more dependents and higher education attenuates the relationship between pay satisfaction and WFC. Copyright © 2012 John Wiley & Sons, Ltd.
Positive affectivity neutralizes transformational leadership's influence on creative performance and organizational citizenship behaviors
Authors: Gilmore Phillip L. , Hu Xiaoxiao , Wei Feng , Tetrick Lois E. , Zaccaro Stephen J.
Published: October 2012

This study uses an interactionist approach to examine the moderating effect of follower trait positive affectivity (trait PA) on the relation between transformational leadership and both follower creative performance and organizational citizenship behaviors (OCB). On the basis of responses from 212 employees and their direct supervisors from the research and development department of a company in Mainland China, results support the hypothesized moderation effect. Specifically, the positive influence of transformational leadership on creative performance was significantly reduced for followers who were higher on trait PA (ΔR2 = .02, p < .05). The same pattern, in which followers' trait PA appeared to substitute for the influence of transformational leadership, generalized to the outcome of follower OCB as well (ΔR2 = .04, p < .01). We discussed theoretical and practical implications of these findings. Copyright © 2012 John Wiley & Sons, Ltd.
A study of subtle motor signs in early Parkinson's disease
Authors: Schneider Susanne A. , Drude Laura , Kasten Meike , Klein Christine , Hagenah Johann
Published: October 2012

Background:

The UPDRS is the most widely used rating scale for Parkinson's disease (PD). However, subtle features of early disease stages may be missed.

Methods:

We studied 25 early PD patients using a newly compiled battery of motor tests focusing on subtle motor features. Focal dystonia patients (n = 31) and healthy individuals (n = 26) served as controls. Specifically, asymmetric shoulder null position and delayed shoulder shrugs, reduced arm swing, subtle tremor, and timed finger taps were assessed. Spiral drawings and writing were also studied.

Results:

With a total mean of 9.8 ± 4.9 (possible range: 0–94), PD patients scored significantly higher than dystonia patients (2.9 ± 2.0) and healthy controls (1.9 ± 2.0) (P < 0.001). Reduced arm swing and tremor of individual fingers best distinguished PD from the other groups.

Conclusions:

The battery was sensitive to detect subtle motor features missed by the UPDRS. For future revisions of an international motor score, further assessment of these items may be worthwhile. © 2012 Movement Disorder Society
Gait patterns in parkinsonian patients with or without mild cognitive impairment
Authors: Amboni Marianna , Barone Paolo , Iuppariello Luigi , Lista Ilaria , Tranfaglia Riccardo , Fasano Alfonso , Picillo Marina , Vitale Carmine , Santangelo Gabriella , Agosti Valeria , Iavarone Alessandro , Sorrentino Giuseppe
Published: October 2012

Although in recent years the relationship between cognition and gait in Parkinson's disease (PD) has received increasing attention, the specific connections between gait patterns and cognitive features are not fully understood. The objective of this study was to describe the gait patterns in patients affected by PD with or without mild cognitive impairment (MCI+ and MCI−, respectively). We also sought to find an association between gait patterns and specific cognitive profiles. Using a gait analysis system, we compared the gait patterns among MCI+ patients (n = 19), MCI− patients (n − 24), and age‐ and sex‐matched healthy subjects (HS; n = 20) under the following conditions: (1) normal gait, (2) motor dual task, and (3) cognitive dual task. In PD patients, gait parameters were evaluated in both the off and on states. Memory, executive, and visuospatial domains were assessed using an extensive neuropsychological battery. Compared with MCI− PD and HS, MCI+ PD patients displayed reduced step length and swing time and impairment of measures of dynamic stability; these dysfunctions were only partially reversed by levodopa. We also found that dual‐task conditions affected several walking parameters in MCI+ PD in the off and on states relative to MCI− PD and HS. Factor analysis revealed 2 independent factors, namely, pace and stability. The latter was strongly and directly correlated to the visuospatial domain. In conclusion, dysfunctions on specific gait parameters, which were poorly responsive to levodopa and highly sensitive to dual‐task conditions, were associated with MCI in PD patients. Importantly, visuospatial impairment was strongly associated with the development of instability and more generally with the progression of PD. © 2012 Movement Disorder Society
NF‐KB activity functions in primary pericytes in a cell‐ and non‐cell‐autonomous manner to affect myotube formation
Authors: Hyldahl Robert D. , Schwartz Lawrence M. , Clarkson Priscilla M.
Published: October 2012

Introduction: Skeletal muscle regeneration following damage relies on proliferation and differentiation of muscle precursor cells (MPCs). We recently observed increased NF‐kB activity in vascular‐associated muscle resident pericytes following muscle damage in humans. We determined how altered NF‐kB activity in human primary pericytes (HPPs) affects their myogenic differentiation (cell‐autonomous effects), as well as proliferation and differentiation of co‐cultured MPCs (non–cell‐autonomous effects). Methods: HPPs were transfected with vectors that increased or decreased NF‐kB activity. Transfected HPPs were co‐cultured with C2C12 myoblasts under differentiation conditions, and HPP fusion to myotubes was measured. We also co‐cultured HPPs with C2C12 myoblasts and measured proliferation and myotube formation. Results: Inhibition of NF‐kB activity increased HPP fusion to C2C12 myotubes. Moreover, enhanced NF‐kB activity in HPPs suppressed differentiation and enhanced proliferation of co‐cultured myoblasts. Conclusions: NF‐kB activity acts cell‐autonomously to inhibit HPP myogenic differentiation and non–cell‐autonomously to promote MPC proliferation and suppress MPC differentiation in vitro. Muscle Nerve, 2013
Lack of caspase‐3 attenuates immobilization‐induced muscle atrophy and loss of tension generation along with mitigation of apoptosis and inflammation
Authors: Zhu Shimei , Nagashima Michio , Khan Mohammed A.S. , Yasuhara Shingo , Kaneki Masao , Martyn J.A. Jeevendra
Published: October 2012

Introduction: Immobilization by casting induces disuse muscle atrophy (DMA). Methods: Using wild type (WT) and caspase‐3 knockout (KO) mice, we evaluated the effect of caspase‐3 on muscle mass, apoptosis, and inflammation during DMA. Results: Caspase‐3 deficiency significantly attenuated muscle mass decrease [gastrocnemius: 28 ± 1% in KO vs. 41 ± 3% in WT; soleus: 47 ± 2% in KO vs. 56 ± 2% in WT; (P < 0.05)] and gastrocnemius twitch tension decrease (23 ± 4% in KO vs. 36 ± 3% in WT, P < 0.05) at day 14 in immobilized vs. contralateral hindlimb. Lack of caspase‐3 decreased immobilization‐induced increased apoptotic myonuclei (3.2‐fold) and macrophage infiltration (2.2‐fold) in soleus muscle and attenuated increased monocyte chemoattractant protein‐1 mRNA expression (2‐fold in KO vs. 18‐fold in WT) in gastrocnemius. Conclusions: Caspase‐3 plays a key role in DMA and associated decreased tension, presumably by acting on the apoptosis and inflammation pathways. Muscle Nerve 47: 711–721, 2013
Impact of pre‐analytical factors on the proteomic analysis of formalin‐fixed paraffin‐embedded tissue
Authors: Thompson Seonaid M. , Craven Rachel A. , Nirmalan Niroshini J. , Harnden Patricia , Selby Peter J. , Banks Rosamonde E.
Published: October 2012

Formalin‐fixed paraffin‐embedded (FFPE) tissue samples represent a tremendous potential resource for biomarker discovery, with large numbers of samples in hospital pathology departments and links to clinical information. However, the cross‐linking of proteins and nucleic acids by formalin fixation has hampered analysis and proteomic studies have been restricted to using frozen tissue, which is more limited in availability as it needs to be collected specifically for research. This means that rare disease subtypes cannot be studied easily. Recently, improved extraction techniques have enabled analysis of FFPE tissue by a number of proteomic techniques. As with all clinical samples, pre‐analytical factors are likely to impact on the results obtained, although overlooked in many studies. The aim of this review is to discuss the various pre‐analytical factors, which include warm and cold ischaemic time, size of sample, fixation duration and temperature, tissue processing conditions, length of storage of archival tissue and storage conditions, and to review the studies that have considered these factors in more detail. In those areas where investigations are few or non‐existent, illustrative examples of the possible importance of specific factors have been drawn from studies using frozen tissue or from immunohistochemical studies of FFPE tissue.
Apolipoprotein A‐I: Insights from redox proteomics for its role in neurodegeneration
Authors: Keeney Jeriel T. R. , Swomley Aaron M. , Förster Sarah , Harris Jessica L. , Sultana Rukhsana , Butterfield D. Allan
Published: October 2012

Proteomics has a wide range of applications, including determination of differences in the proteome in terms of expression and post‐translational protein modifications. Redox proteomics allows the identification of specific targets of protein oxidation in a biological sample. Using proteomic techniques, apolipoprotein A‐I (ApoA‐I) has been found at decreased levels in subjects with a variety of neurodegenerative disorders including in the serum and cerebrospinal fluid (CSF) of Alzheimer disease (AD), Parkinson disease (PD), and Down syndrome (DS) with gout subjects. ApoA‐I plays roles in cholesterol transport and regulation of inflammation. Redox proteomics further showed ApoA‐I to be highly oxidatively modified and particularly susceptible to modification by 4‐hydroxy‐2‐trans‐nonenal (HNE), a lipid peroxidation product. In the current review, we discuss the consequences of oxidation of ApoA‐I in terms of neurodegeneration. ROS‐associated chemotherapy related ApoA‐I oxidation leads to elevation of peripheral levels of tumor necrosis factor‐α (TNF‐α) that can cross the blood‐brain barrier (BBB) causing a signaling cascade that can contribute to neuronal death, likely a contributor to what patients refer to as “chemobrain.” Current evidence suggests ApoA‐I to be a promising diagnostic marker as well as a potential target for therapeutic strategies in these neurodegenerative disorders.
Distinctive gas‐phase fragmentation pathway of the mitorubramines, novel secondary metabolites from Hypoxylon fragiforme
Authors: Svilar Ljubica , Stankov‐Jovanovic Vesna , Stadler Marc , Nedev Hristo , Tabet Jean‐Claude
Published: October 2012

RATIONALE

Azaphilones, belonging to the class of mitorubrins usually produced in Hypoxylon fragiforme, react easily with amino groups, giving amine derivatives, mitorubramines. These secondary metabolites exhibit a wide range of biological activities. Finding new secondary metabolites from fungi is important, and electrospray ionization (ESI) high‐resolution mass spectrometry (HRMS) coupled with sequential MSn experiments has become a method of choice for the chemotaxonomic classification of fungi.

METHODS

High‐performance liquid chromatography of methanol extracts coupled to positive electrospray ionization, high resolving power for accurate mass measurements and resonant excitation for selective ion collision‐induced dissociation (CID) have been conducted with the aim of resolving the structures of possible novel compounds.

RESULTS

Soft desolvation conditions in the ESI source enabled the detection of intact mitorubramines present in the extract. HRMS provided unambiguous information about the elemental composition of the mitorubramines and their product ions, while sequential MS3 experiments were essential for the structural discernment of already reported mitorubrins and newly discovered mitorubramines. Indeed, specifically from the latter, a series of consecutive dissociations takes place under CID conditions that are useful for structural elucidation.

CONCLUSIONS

A distinctive method for two families of secondary metabolites has been developed. Information observed using HRMS and sequential MSn experiments gave unambiguous information about the structure of mitorubramines, especially the position of the nitrogen atom, which was strengthened by proposed unusual fragmentation mechanisms, such as the rearrangement yielding the release of CO2 from the hydroxyl‐diketone structures. These experiments demonstrated that the fragmentations are facilitated by the nitrogen electron lone‐pair in mitorubramines, which does not occur in mitorubrins. Copyright © 2012 John Wiley & Sons, Ltd.
Nanostructured Superhydrophobic Substrates Trigger the Development of 3D Neuronal Networks
Authors: Limongi Tania , Cesca Fabrizia , Gentile Francesco , Marotta Roberto , Ruffilli Roberta , Barberis Andrea , Dal Maschio Marco , Petrini Enrica Maria , Santoriello Stefania , Benfenati Fabio , Di Fabrizio Enzo
Published: October 2012

The generation of 3D networks of primary neurons is a big challenge in neuroscience. Here, a novel method is presented for a 3D neuronal culture on superhydrophobic (SH) substrates. How nano‐patterned SH devices stimulate neurons to build 3D networks is investigated. Scanning electron microscopy and confocal imaging show that soon after plating neurites adhere to the nanopatterned pillar sidewalls and they are subsequently pulled between pillars in a suspended position. These neurons display an enhanced survival rate compared to standard cultures and develop mature networks with physiological excitability. These findings underline the importance of using nanostructured SH surfaces for directing 3D neuronal growth, as well as for the design of biomaterials for neuronal regeneration.
Kriterien für die Produktauswahl bei Stahlbau‐Hohlprofilen
Authors: Bach Kirstin
Published: October 2012

Mit der Auswahl der richtigen Hohlprofile werden Verhalten und Tragfähigkeit einer Konstruktion deutlich verbessert. Stahlbau‐Hohlprofile können entweder warm‐ oder kaltgefertigt hergestellt werden und aufgrund der verschiedenen Herstellungsprozesse haben die beiden Typen unterschiedliche technische Eigenschaften.

Bei Tata Steel Europe erfolgt die Produktion nach beiden Prozessen, deshalb werden in diesem Beitrag die Hauptunterschiede dieser zwei Hohlprofilarten erläutert, um eine sinnvolle und gezielte Produktauswahl zu ermöglichen.
Integrable superstrings on the squashed three-sphere
Authors: Orlando Domenico , Uruchurtu Linda I.
Published: October 2012

Abstract

In this note we study type ii superstring theory on the direct product of AdS3, the squashed three-sphere and a four-torus (AdS3 × SqS3 × T
4). We derive explicitly the Green-Schwarz action and discuss in detail the hidden integrable structure corresponding to local and non-local currents. We find that the model is classically integrable and that the currents generate a full psu(1, 1|2) superalgebra, even though the corresponding spacetime isometries are broken by the squashing.
Surface Functionalized Nanofibrillar Cellulose (NFC) Film as a Platform for Immunoassays and Diagnostics
Authors: Orelma Hannes , Filpponen Ilari , Johansson Leena-Sisko , Österberg Monika , Rojas Orlando J. , Laine Janne
Published: October 2012

We introduce a new method to modify films of nanofibrillated cellulose (NFC) to produce non-porous, water-resistant substrates for diagnostics. First, water resistant NFC films were prepared from mechanically disintegrated NFC hydrogel, and then their surfaces were carboxylated via TEMPO-mediated oxidation. Next, the topologically functionalized film was activated via EDS/NHS chemistry, and its reactivity verified with bovine serum albumin and antihuman IgG. The surface carboxylation, EDC/NHS activation and the protein attachment were confirmed using quartz crystal microbalance with dissipation, contact angle measurements, conductometric titrations, X-ray photoelectron spectroscopy and fluorescence microscopy. The surface morphology of the prepared films was investigated using confocal laser scanning microscopy and atomic force microscopy. Finally, we demonstrate that antihuman IgG can be immobilized on the activated NFC surface using commercial piezoelectric inkjet printing.
Physical modeling of tsunamis generated by three‐dimensional deformable granular landslides
Authors: Mohammed Fahad , Fritz Hermann M.
Published: October 2012

Tsunamis generated by deformable granular landslides are physically modeled in a three‐dimensional tsunami wave basin based on the generalized Froude similarity. The dynamic landslide impact characteristics were controlled by means of a novel pneumatic landslide generator. The wave amplitudes, periods, and wavelengths are related to the landslide parameters at impact with the landslide Froude number being a dominant parameter. Between 1 and 15% of the landslide kinetic energy at impact is converted into the wave train energy. The wave amplitudes decay in radial and angular directions from the landslide axis. The first wave crest mostly travels with speeds close to the theoretical approximation of the solitary wave speed. The measured tsunami wave profiles were either of the nonlinear oscillatory or nonlinear transition type depending primarily on the landslide Froude number and relative slide thickness at impact. The generated waves range from shallow to deep water depth regimes, with the majority being in the intermediate water depth regime. Wave characteristics are compared with other two‐ and three‐dimensional landslide tsunami studies and the results are discussed.
Ice sheet sources of sea level rise and freshwater discharge during the last deglaciation
Authors: Carlson Anders E. , Clark Peter U.
Published: October 2012

We review and synthesize the geologic record that constrains the sources of sea level rise and freshwater discharge to the global oceans associated with retreat of ice sheets during the last deglaciation. The Last Glacial Maximum (∼26–19 ka) was terminated by a rapid 5–10 m sea level rise at 19.0–19.5 ka, sourced largely from Northern Hemisphere ice sheet retreat in response to high northern latitude insolation forcing. Sea level rise of 8–20 m from ∼19 to 14.5 ka can be attributed to continued retreat of the Laurentide and Eurasian Ice Sheets, with an additional freshwater forcing of uncertain amount delivered by Heinrich event 1. The source of the abrupt acceleration in sea level rise at ∼14.6 ka (meltwater pulse 1A, ∼14–15 m) includes contributions of 6.5–10 m from Northern Hemisphere ice sheets, of which 2–7 m represents an excess contribution above that derived from ongoing ice sheet retreat. Widespread retreat of Antarctic ice sheets began at 14.0–15.0 ka, which, together with geophysical modeling of far‐field sea level records, suggests an Antarctic contribution to this meltwater pulse as well. The cause of the subsequent Younger Dryas cold event can be attributed to eastward freshwater runoff from the Lake Agassiz basin to the St. Lawrence estuary that agrees with existing Lake Agassiz outlet radiocarbon dates. Much of the early Holocene sea level rise can be explained by Laurentide and Scandinavian Ice Sheet retreat, with collapse of Laurentide ice over Hudson Bay and drainage of Lake Agassiz basin runoff at ∼8.4–8.2 ka to the Labrador Sea causing the 8.2 ka event.
Nighttime D region electron density measurements from ELF‐VLF tweek radio atmospherics recorded at low latitudes
Authors: Maurya Ajeet K. , Veenadhari B. , Singh Rajesh , Kumar Sushil , Cohen M. B. , Selvakumaran R. , Gokani Sneha , Pant P. , Singh A. K. , Inan Umran S.
Published: October 2012

Dispersive atmospherics (tweeks) observed during 2010 simultaneously at two low‐latitude stations, Allahabad (geomagnetic latitude, 16.05°N) and Nainital (geomagnetic latitude, 20.48°N), have been used to estimate the nighttime D region electron density at the ionospheric reflection height under the local nighttime propagation (21:00–02:00 LT or 15:30–20:30 UT). The analysis of simultaneously recorded tweeks at both the stations on five international quiet days during one month each from summer (June), winter (January), and equinox (March) seasons shows that the D region electron density varies 21.5–24.5 cm−3 over the ionospheric reflection height of 85–95 km. The average values of Wait lower ionospheric parameters: ionospheric reference height h′ and sharpness factor β are almost same during winter (85.9–86.1 km, 0.51–0.52 km−1) and equinox (85.6–85.7 km, 0.54 km−1) seasons. The values of h′ and β during summer season are about 83.5 km and 0.60 km−1at both stations. Overall, equivalent electron density profile obtained using tweek method shows lower values of electron density by about 5–60% than those obtained using the International Reference Ionosphere (IRI‐2007) model and lower/higher by 2–68% than those obtained using rocket technique. The electron density estimated using all three techniques (tweek, IRI‐2007, and rocket) is consistent in the altitude range of 82–98 km. The estimated geographic locations of causative lightnings of tweeks were matched with the locations and times of lightnings detected by the World‐Wide Lightning Location Network (WWLLN). The WWLLN detected about 27.5% of causative lightnings of tweeks simultaneously observed at both the stations.
Middle and upper thermosphere density structures due to nonmigrating tides
Authors: Forbes Jeffrey M. , Zhang Xiaoli , Bruinsma Sean
Published: October 2012

Density measurements from the SETA satellites near 200 km during 1982–1984, and the CHAMP and GRACE satellites between 350 and 550 km during 2002–2009, are used to investigate longitudinal structures in density due to nonmigrating tides, and to evaluate performance of the recently‐created Climatological Tidal Model of the Thermosphere (CTMT). Amplitudes for the diurnal and semidiurnal tidal components fall roughly in the range of 4–10%. Diurnal tides at middle and low latitudes are often characterized by wave‐3 and/or wave‐4 structures, consistent with the presence of the eastward‐propagating diurnal tides with zonal wave numberss = 2 and s = 3 (DE2 and DE3, respectively) and with expected seasonal variability based on previous works. Semidiurnal structures often reflect the presence of the eastward‐propagating tide withs = 2 (SE2), which gives rise to wave‐4 structures that have a more antisymmetric relationship between N. and S. hemispheres. Similarities in structures between different years underscore the fact that the thermosphere is subject to repeatable and reproducible forcing by upward‐propagating tides, but there are also occasions where considerable departures from climatology occur. Wave‐2 structures at high latitudes likely contain signatures of the eastward‐propagating diurnal tide withs = 1 (DE1) and the zonally‐symmetric (s = 0) semidiurnal oscillation (S0) propagating upwards from below, but these and other waves that produce wave‐2 can also be forced in‐situ by high‐latitude processes. The CTMT captures the salient features of the observations at middle and low latitudes, although with lower amplitudes that are likely due to phase cancelation effects resulting from averaging over multiple years (2002–2006). We propose that some discrepancies between the CTMT and our observational results may be associated with wave components arising in‐situ in the thermosphere as the result of nonlinear tide‐tide interactions and plasma neutral interactions, the latter being especially prominent at high latitudes where the displaced geomagnetic frame is particularly influential. Modeling studies are required to validate these proposed mechanisms, however.
CKIP‐1 couples Smurf1 ubiquitin ligase with Rpt6 subunit of proteasome to promote substrate degradation
Authors: Wang Yifang , Nie Jing , Wang Yiwu , Zhang Luo , Lu Kefeng , Xing Guichun , Xie Ping , He Fuchu , Zhang Lingqiang
Published: October 2012

CKIP‐1 is an activator of the Smurf1 ubiquitin ligase acting to promote the ubiquitylation of Smad5 and MEKK2. The mechanisms involved in the recognition and degradation of these substrates by the proteasome remain unclear. Here, we show that CKIP‐1, through its leucine zipper, interacts directly with the Rpt6 ATPase of the 19S regulatory particle of the proteasome. CKIP‐1 mediates the Smurf1–Rpt6 interaction and delivers the ubiquitylated substrates to the proteasome. Depletion of CKIP‐1 reduces the degradation of Smurf1 and its substrates by Rpt6. These findings reveal an unexpected adaptor role of CKIP‐1 in coupling the ubiquitin ligase and the proteasome.
Functional anatomy of neural circuits regulating fear and extinction
Authors: Knapska Ewelina , Macias Matylda , Mikosz Marta , Nowak Aleksandra , Owczarek Dorota , Wawrzyniak Marcin , Pieprzyk Marcelina , Cymerman Iwona A. , Werka Tomasz , Sheng Morgan , Maren Stephen , Jaworski Jacek , Kaczmarek Leszek
Published: October 2012

The memory of fear extinction is context dependent: fear that is suppressed in one context readily renews in another. Understanding of the underlying neuronal circuits is, therefore, of considerable clinical relevance for anxiety disorders. Prefrontal cortical and hippocampal inputs to the amygdala have recently been shown to regulate the retrieval of fear memories, but the cellular organization of these projections remains unclear. By using anterograde tracing in a transgenic rat in which neurons express a dendritically-targeted PSD-95:Venus fusion protein under the control of a c-
fos
promoter, we found that, during the retrieval of extinction memory, the dominant input to active neurons in the lateral amygdala was from the infralimbic cortex, whereas the retrieval of fear memory was associated with greater hippocampal and prelimbic inputs. This pattern of retrieval-related afferent input was absent in the central nucleus of the amygdala. Our data show functional anatomy of neural circuits regulating fear and extinction, providing a framework for therapeutic manipulations of these circuits.
A noncoding RNA regulates the neurogenin1 gene locus during mouse neocortical development
Authors: Onoguchi Masahiro , Hirabayashi Yusuke , Koseki Haruhiko , Gotoh Yukiko
Published: October 2012

The proneural basic helix–loop–helix (bHLH) transcription factor neurogenin1 (Neurog1) plays a pivotal role in neuronal differentiation during mammalian development. The spatiotemporal control of the
Neurog1
gene expression is mediated by several specific enhancer elements, although how these elements regulate the
Neurog1
locus has remained largely unclear. Recently it has been shown that a large number of enhancer elements are transcribed, but the regulation and function of the resulting transcripts have been investigated for only several such elements. We now show that an enhancer element located 5.8–7.0 kb upstream of the mouse
Neurog1
locus is transcribed. The production of this transcript, designated
utNgn1
, is highly correlated with that of
Neurog1
mRNA during neuronal differentiation. Moreover, knockdown of
utNgn1
by a corresponding short interfering RNA inhibits the production of
Neurog1
mRNA in response to induction of neuronal differentiation. We also found that production of
utNgn1
is suppressed by polycomb group (PcG) proteins, which inhibit the expression of
Neurog1
. Our results thus suggest that a noncoding RNA transcribed from an enhancer element positively regulates transcription at the
Neurog1
locus.
Transcriptional repressor PRR5 directly regulates clock-output pathways
Authors: Nakamichi Norihito , Kiba Takatoshi , Kamioka Mari , Suzuki Takamasa , Yamashino Takafumi , Higashiyama Tetsuya , Sakakibara Hitoshi , Mizuno Takeshi
Published: October 2012

The circadian clock is an endogenous time-keeping mechanism that enables organisms to adapt to external daily cycles. The clock coordinates biological activities with these cycles, mainly through genome-wide gene expression. However, the exact mechanism underlying regulation of circadian gene expression is poorly understood. Here we demonstrated that an
Arabidopsis
PSEUDO-RESPONSE REGULATOR 5 (PRR5), which acts in the clock genetic circuit, directly regulates expression timing of key transcription factors involved in clock-output pathways. A transient expression assay and ChIP-quantitative PCR assay using mutated PRR5 indicated that PRR5 associates with target DNA through binding at the CCT motif in vivo. ChIP followed by deep sequencing coupled with genome-wide expression profiling revealed the direct-target genes of PRR5. PRR5 direct-targets include genes encoding transcription factors involved in flowering-time regulation, hypocotyl elongation, and cold-stress responses. PRR5-target gene expression followed a circadian rhythm pattern with low, basal expression from noon until midnight, when PRR9, PRR7, and PRR5 were expressed. ChIP-quantitative PCR assays indicated that PRR7 and PRR9 bind to the direct-targets of PRR5. Genome-wide expression profiling using a
prr9 prr7 prr5
triple mutant suggests that PRR5, PRR7, and PRR9 repress these targets. Taken together, our results illustrate a genetic network in which PRR5, PRR7, and PRR9 directly regulate expression timing of key transcription factors to coordinate physiological processes with daily cycles.
Evidence for the respiration of ancient terrestrial organic C in northern temperate lakes and streams
Authors: McCallister S. Leigh , del Giorgio Paul A.
Published: October 2012

Northern rivers and lakes process large quantities of organic and inorganic carbon from the surrounding terrestrial ecosystems. These external carbon inputs fuel widespread CO
2
supersaturation in continental waters, and the resulting CO
2
emissions from lakes and rivers are now recognized as a globally significant loss of terrestrial production to the atmosphere. Whereas the magnitude of emissions has received much attention, the pathways of C delivery and processing that generate these emissions are still not well-understood. CO
2
outgassing in aquatic systems has been unequivocally linked to microbial degradation and respiration of terrestrial organic carbon (OC), but the nature (i.e., age and source) of this OC respired in surface waters is largely unknown. We present direct radiocarbon measurements of OC respired by bacteria in freshwater aquatic systems, specifically temperate lakes and streams in Québec. Terrestrial OC fuels much of the respiration in these systems, and our results show that a significant fraction of the respired terrestrial OC is old (in the range of 1,000–3,000 y B.P.). Because the bulk OC pools in these lakes is relatively young, our results also suggest selective removal of an old but highly bioreactive terrestrial OC pool and its conversion to CO
2
by bacteria. The respiration of ancient
14
C-depleted terrestrial C in northern lakes and rivers provides a biological link between contemporary aquatic carbon biogeochemistry and paleo-conditions in the watershed, and it implies the aquatic-mediated return to the atmosphere of C putatively considered permanently stored, thus challenging current models of long-term C storage in terrestrial reservoirs.
Modified SH2 domain to phototrap and identify phosphotyrosine proteins from subcellular sites within cells
Authors: Uezu Akiyoshi , Okada Hirokazu , Murakoshi Hideji , del Vescovo Cosmo D. , Yasuda Ryohei , Diviani Dario , Soderling Scott H.
Published: October 2012

Spatial regulation of tyrosine phosphorylation is important for many aspects of cell biology. However, phosphotyrosine accounts for less than 1% of all phosphorylated substrates, and it is typically a very transient event in vivo. These factors complicate the identification of key tyrosine kinase substrates, especially in the context of their extraordinary spatial organization. Here, we describe an approach to identify tyrosine kinase substrates based on their subcellular distribution from within cells. This method uses an unnatural amino acid-modified Src homology 2 (SH2) domain that is expressed within cells and can covalently trap phosphotyrosine proteins on exposure to light. This SH2 domain-based photoprobe was targeted to cellular structures, such as the actin cytoskeleton, mitochondria, and cellular membranes, to capture tyrosine kinase substrates unique to each cellular region. We demonstrate that RhoA, one of the proteins associated with actin, can be phosphorylated on two tyrosine residues within the switch regions, suggesting that phosphorylation of these residues might modulate RhoA signaling to the actin cytoskeleton. We conclude that expression of SH2 domains within cellular compartments that are capable of covalent phototrapping can reveal the spatial organization of tyrosine kinase substrates that are likely to be important for the regulation of subcellular structures.
Correlating microbial community profiles with geochemical data in highly stratified sediments from the Arctic Mid-Ocean Ridge
Authors: Jorgensen Steffen Leth , Hannisdal Bjarte , Lanzén Anders , Baumberger Tamara , Flesland Kristin , Fonseca Rita , Øvreås Lise , Steen Ida H. , Thorseth Ingunn H. , Pedersen Rolf B. , Schleper Christa
Published: October 2012

Microbial communities and their associated metabolic activity in marine sediments have a profound impact on global biogeochemical cycles. Their composition and structure are attributed to geochemical and physical factors, but finding direct correlations has remained a challenge. Here we show a significant statistical relationship between variation in geochemical composition and prokaryotic community structure within deep-sea sediments. We obtained comprehensive geochemical data from two gravity cores near the hydrothermal vent field Loki’s Castle at the Arctic Mid-Ocean Ridge, in the Norwegian-Greenland Sea. Geochemical properties in the rift valley sediments exhibited strong centimeter-scale stratigraphic variability. Microbial populations were profiled by pyrosequencing from 15 sediment horizons (59,364 16S rRNA gene tags), quantitatively assessed by qPCR, and phylogenetically analyzed. Although the same taxa were generally present in all samples, their relative abundances varied substantially among horizons and fluctuated between Bacteria- and Archaea-dominated communities. By independently summarizing covariance structures of the relative abundance data and geochemical data, using principal components analysis, we found a significant correlation between changes in geochemical composition and changes in community structure. Differences in organic carbon and mineralogy shaped the relative abundance of microbial taxa. We used correlations to build hypotheses about energy metabolisms, particularly of the Deep Sea Archaeal Group, specific Deltaproteobacteria, and sediment lineages of potentially anaerobic Marine Group I Archaea. We demonstrate that total prokaryotic community structure can be directly correlated to geochemistry within these sediments, thus enhancing our understanding of biogeochemical cycling and our ability to predict metabolisms of uncultured microbes in deep-sea sediments.
Crystal structure of Enpp1, an extracellular glycoprotein involved in bone mineralization and insulin signaling
Authors: Kato Kazuki , Nishimasu Hiroshi , Okudaira Shinichi , Mihara Emiko , Ishitani Ryuichiro , Takagi Junichi , Aoki Junken , Nureki Osamu
Published: October 2012

Enpp1 is a membrane-bound glycoprotein that regulates bone mineralization by hydrolyzing extracellular nucleotide triphosphates to produce pyrophosphate. Enpp1 dysfunction causes human diseases characterized by ectopic calcification. Enpp1 also inhibits insulin signaling, and an Enpp1 polymorphism is associated with insulin resistance. However, the precise mechanism by which Enpp1 functions in these cellular processes remains elusive. Here, we report the crystal structures of the extracellular region of mouse Enpp1 in complex with four different nucleotide monophosphates, at resolutions of 2.7–3.2 Å. The nucleotides are accommodated in a pocket formed by an insertion loop in the catalytic domain, explaining the preference of Enpp1 for an ATP substrate. Structural mapping of disease-associated mutations indicated the functional importance of the interdomain interactions. A structural comparison of Enpp1 with Enpp2, a lysophospholipase D, revealed marked differences in the domain arrangements and active-site architectures. Notably, the Enpp1 mutant lacking the insertion loop lost the nucleotide-hydrolyzing activity but instead gained the lysophospholipid-hydrolyzing activity of Enpp2. Our findings provide structural insights into how the Enpp family proteins evolved to exert their diverse cellular functions.
Modification of RelA by O
-
linked
N
-acetylglucosamine links glucose metabolism to NF-κB acetylation and transcription
Authors: Allison David F. , Wamsley J. Jacob , Kumar Manish , Li Duo , Gray Lisa G. , Hart Gerald W. , Jones David R. , Mayo Marty W.
Published: October 2012

The molecular mechanisms linking glucose metabolism with active transcription remain undercharacterized in mammalian cells. Using nuclear factor-κB (NF-κB) as a glucose-responsive transcription factor, we show that cells use the hexosamine biosynthesis pathway and O-linked β-
N
-acetylglucosamine (
O
-GlcNAc) transferase (OGT) to potentiate gene expression in response to tumor necrosis factor (TNF) or etoposide. Chromatin immunoprecipitation assays demonstrate that, upon induction, OGT localizes to NF-κB–regulated promoters to enhance RelA acetylation. Knockdown of OGT abolishes p300-mediated acetylation of RelA on K310, a posttranslational mark required for full NF-κB transcription. Mapping studies reveal T305 as an important residue required for attachment of the
O
-GlcNAc moiety on RelA. Furthermore, p300 fails to acetylate a full-length RelA(T305A) mutant, linking
O-
GlcNAc and acetylation events on NF-κB. Reconstitution of RelA null cells with the RelA(T305A) mutant illustrates the importance of this residue for NF-κB–dependent gene expression and cell survival. Our work provides evidence for a unique regulation where attachment of the
O-
GlcNAc moiety to RelA potentiates p300 acetylation and NF-κB transcription.
Using intein catalysis to probe the origin of major histocompatibility complex class I-presented peptides
Authors: Farfán-Arribas Diego J. , Stern Lawrence J. , Rock Kenneth L.
Published: October 2012

All vertebrate nucleated cells generate peptides from their expressed gene products and then display them at the cell surface bound to MHC class I molecules. This allows CD8+T cells to detect and eliminate abnormal cells that are synthesizing foreign proteins, e.g., from viruses or mutations. To permit the immune system to more uniformly monitor a cell's proteins, regardless of their half-life or location, it has been thought that the products of rapid degradation of the mistakes of protein synthesis (defective ribosomal products, DRiPs) preferentially contribute to the class I-presented peptides. However, using intein catalysis to generate peptide sequences exclusively by posttranslational splicing of mature proteins, we show here that presented peptides can be generated from fully folded and functional proteins. Remarkably, the presentation of peptides from two model mature proteins is just as efficient as from newly synthesized proteins subject to errors in translation or folding. These results indicate that for the constructs we have analyzed, DRiPs are not a more efficient source of class I peptides for antigen presentation than the turnover of mature functional proteins. Accordingly, our data suggest that one of the major ways the immune system evaluates the health of cells is by monitoring the breakdown products of the proteome.
Alphaherpesvirus axon-to-cell spread involves limited virion transmission
Authors: Taylor Matthew P. , Kobiler Oren , Enquist Lynn W.
Published: October 2012

The spread of viral infection within a host can be restricted by bottlenecks that limit the size and diversity of the viral population. An essential process for alphaherpesvirus infection is spread from axons of peripheral nervous system neurons to cells in peripheral epithelia (anterograde-directed spread, ADS). ADS is necessary for the formation of vesicular lesions characteristic of reactivated herpesvirus infections; however, the number of virions transmitted is unknown. We have developed two methods to quantitate ADS events using a compartmentalized neuronal culture system. The first method uses HSV-1 and pseudorabies virus recombinants that express one of three different fluorescent proteins. The fluorescence profiles of cells infected with the virus mixtures are used to quantify the number of expressed viral genomes. Strikingly, although epithelial or neuronal cells express 3–10 viral genomes after infection by free virions, epithelial cells infected by HSV-1 or pseudorabies virus following ADS express fewer than two viral genomes. The second method uses live-cell fluorescence microscopy to track individual capsids involved in ADS. We observed that most ADS events involve a single capsid infecting a target epithelial cell. Together, these complementary analyses reveal that ADS events are restricted to small numbers of viral particles, most often a single virion, resulting in a single viral genome initiating infection.