bluuebunny/crossref_metadata_2025 huggingface dataset:
Extended local similarity analysis (eLSA) of microbial community and other time series data with replicates
Authors: Xia Li C , Steele Joshua A , Cram Jacob A , Cardon Zoe G , Simmons Sheri L , Vallino Joseph J , Fuhrman Jed A , Sun Fengzhu
Published: December 2011

Background

The increasing availability of time series microbial community data from metagenomics and other molecular biological studies has enabled the analysis of large-scale microbial co-occurrence and association networks. Among the many analytical techniques available, the Local Similarity Analysis (LSA) method is unique in that it captures local and potentially time-delayed co-occurrence and association patterns in time series data that cannot otherwise be identified by ordinary correlation analysis. However LSA, as originally developed, does not consider time series data with replicates, which hinders the full exploitation of available information. With replicates, it is possible to understand the variability of local similarity (LS) score and to obtain its confidence interval.

Results

We extended our LSA technique to time series data with replicates and termed it extended LSA, or eLSA. Simulations showed the capability of eLSA to capture subinterval and time-delayed associations. We implemented the eLSA technique into an easy-to-use analytic software package. The software pipeline integrates data normalization, statistical correlation calculation, statistical significance evaluation, and association network construction steps. We applied the eLSA technique to microbial community and gene expression datasets, where unique time-dependent associations were identified.

Conclusions

The extended LSA analysis technique was demonstrated to reveal statistically significant local and potentially time-delayed association patterns in replicated time series data beyond that of ordinary correlation analysis. These statistically significant associations can provide insights to the real dynamics of biological systems. The newly designed eLSA software efficiently streamlines the analysis and is freely available from the eLSA homepage, which can be accessed at http://meta.usc.edu/softs/lsa.
Cerebral perfusion pressure, microdialysis biochemistry and clinical outcome in patients with traumatic brain injury
Authors: Paraforou Theoniki , Paterakis Konstantinos , Fountas Konstantinos , Paraforos George , Chovas Achilleas , Tasiou Anastasia , Mpakopoulou Maria , Papadopoulos Dimitrios , Karavellis Antonios , Komnos Apostolos
Published: December 2011

Background

Traumatic Brain Injury (TBI) is a major cause of death and disability. It has been postulated that brain metabolic status, intracranial pressure (ICP) and cerebral perfusion pressure (CPP) are related to patients' outcome. The aim of this study was to investigate the relationship between CPP, ICP and microdialysis parameters and clinical outcome in TBIs.

Results

Thirty four individuals with severe brain injury hospitalized in an intensive care unit participated in this study. Microdialysis data were collected, along with ICP and CPP values. Glasgow Outcome Scale (GOS) was used to evaluate patient outcome at 6 months after injury. Fifteen patients with a CPP greater than 75 mmHg, L/P ratio lower than 37 and Glycerol concentration lower than 72 mmol/l had an excellent outcome (GOS 4 or 5), as opposed to the remaining 19 patients. No patient with a favorable outcome had a CPP lower than 75 mmHg or Glycerol concentration and L/P ratio greater than 72 mmol/l and 37 respectively. Data regarding L/P ratio and Glycerol concentration were statistically significant at p = 0.05 when patients with favorable and unfavorable outcome were compared. In a logistic regression model adjusted for age, sex and Glasgow Coma Scale on admission, a CPP greater than 75 mmHg was marginally statistically significantly related to outcome at 6 months after injury.

Conclusions

Patients with favorable outcome had certain common features in terms of microdialysis parameters and CPP values. An individualized approach regarding CPP levels and cut -off points for Glycerol concentration and L/P ratio are proposed.
Agrobacterium tumefaciens-mediated transformation of Aspergillus aculeatus for insertional mutagenesis
Authors: Kunitake Emi , Tani Shuji , Sumitani Jun-ichi , Kawaguchi Takashi
Published: December 2011

Agrobacterium tumefaciens-mediated transformation (AMT) was applied to Aspergillus aculeatus. Transformants carrying the T-DNA from a binary vector pBIG2RHPH2 were sufficiently mitotically stable to allow functional genomic analyses. The AMT technique was optimized by altering the concentration of acetosyringone, the ratio and concentration of A. tumefaciens and A. aculeatus cells, the duration of co-cultivation, and the status of A. aculeatus cells when using conidia, protoplasts, or germlings. On average, 30 transformants per 104 conidia or 217 transformants per 107 conidia were obtained under the optimized conditions when A. tumefaciens co-cultured with fungi using solid or liquid induction media (IM). Although the transformation frequency in liquid IM was 100-fold lower than that on solid IM, the AMT method using liquid IM is better suited for high-throughput insertional mutagenesis because the transformants can be isolated on fewer selection media plates by concentrating the transformed germlings. The production of two albino A. aculeatus mutants by AMT confirmed that the inserted T-DNA disrupted the polyketide synthase gene AapksP, which is involved in pigment production. Considering the efficiency of AMT and the correlation between the phenotypes and genotypes of the transformants, the established AMT technique offers a highly efficient means for characterizing the gene function in A. aculeatus.
Landscape of somatic allelic imbalances and copy number alterations in HER2-amplified breast cancer
Authors: Staaf Johan , Jönsson Göran , Ringnér Markus , Baldetorp Bo , Borg Åke
Published: December 2011

Introduction

Human epidermal growth factor receptor 2 (HER2)-amplified breast cancer represents a clinically well-defined subgroup due to availability of targeted treatment. However, HER2-amplified tumors have been shown to be heterogeneous at the genomic level by genome-wide microarray analyses, pointing towards a need of further investigations for identification of recurrent copy number alterations and delineation of patterns of allelic imbalance.

Methods

High-density whole genome array-based comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) array data from 260 HER2-amplified breast tumors or cell lines, and 346 HER2-negative breast cancers with molecular subtype information were assembled from different repositories. Copy number alteration (CNA), loss-of-heterozygosity (LOH), copy number neutral allelic imbalance (CNN-AI), subclonal CNA and patterns of tumor DNA ploidy were analyzed using bioinformatical methods such as genomic identification of significant targets in cancer (GISTIC) and genome alteration print (GAP). The patterns of tumor ploidy were confirmed in 338 unrelated breast cancers analyzed by DNA flow cytometry with concurrent BAC aCGH and gene expression data.

Results

A core set of 36 genomic regions commonly affected by copy number gain or loss was identified by integrating results with a previous study, together comprising > 400 HER2-amplified tumors. While CNN-AI frequency appeared evenly distributed over chromosomes in HER2-amplified tumors, not targeting specific regions and often < 20% in frequency, the occurrence of LOH was strongly associated with regions of copy number loss. HER2-amplified and HER2-negative tumors stratified by molecular subtypes displayed different patterns of LOH and CNN-AI, with basal-like tumors showing highest frequencies followed by HER2-amplified and luminal B cases. Tumor aneuploidy was strongly associated with increasing levels of LOH, CNN-AI, CNAs and occurrence of subclonal copy number events, irrespective of subtype. Finally, SNP data from individual tumors indicated that genomic amplification in general appears as monoallelic, that is, it preferentially targets one parental chromosome in HER2-amplified tumors.

Conclusions

We have delineated the genomic landscape of CNAs, amplifications, LOH, and CNN-AI in HER2-amplified breast cancer, but also demonstrated a strong association between different types of genomic aberrations and tumor aneuploidy irrespective of molecular subtype.
Soluble urokinase-type plasminogen activator receptor levels in patients with burn injuries and inhalation trauma requiring mechanical ventilation: an observational cohort study
Authors: Backes Yara , van der Sluijs Koenraad F , Tuip de Boer Anita M , Hofstra Jorrit Jan , Vlaar Alexander PJ , Determann Rogier M , Knape Paul , Mackie David P , Schultz Marcus J
Published: December 2011

Introduction

Soluble urokinase-type plasminogen activator receptor (suPAR) has been proposed as a biologic marker of fibrinolysis and inflammation. The aim of this study was to investigate the diagnostic and prognostic value of systemic and pulmonary levels of suPAR in burn patients with inhalation trauma who need mechanical ventilation.

Methods

suPAR was measured in plasma and nondirected lung-lavage fluid of mechanically ventilated burn patients with inhalation trauma. The samples were obtained on the day of inhalation trauma and on alternate days thereafter until patients were completely weaned from the mechanical ventilator. Mechanically ventilated patients without burns and without pulmonary disease served as controls.

Results

Systemic levels of suPAR in burn patients with inhalation trauma were not different from those in control patients. On admission and follow up, pulmonary levels of suPAR in patients with inhalation trauma were significantly higher compared with controls. Pulmonary levels of suPAR highly correlated with pulmonary levels of interleukin 6, a marker of inflammation, and thrombin-antithrombin complexes, markers of coagulation, but not plasminogen activator activity, a marker of fibrinolysis. Systemic levels of suPAR were predictive of the duration of mechanical ventilation and length of intensive care unit (ICU) stay. Duration of mechanical ventilation and length of ICU stay were significantly longer in burn-injury patients with systemic suPAR levels > 9.5 ng/ml.

Conclusions

Pulmonary levels of suPAR are elevated in burn patients with inhalation trauma, and they correlate with pulmonary inflammation and coagulation. Although pulmonary levels of suPAR may have diagnostic value in burn-injury patients, systemic levels of suPAR have prognostic value.
Contribution of Nutritional Deficit to the Pathogenesis of the Nonthyroidal Illness Syndrome in Critical Illness: A Rabbit Model Study
Authors: Mebis Liese , Eerdekens An , Güiza Fabian , Princen Leslie , Derde Sarah , Vanwijngaerden Yoo-Mee , Vanhorebeek Ilse , Darras Veerle M. , Van den Berghe Greet , Langouche Lies
Published: December 2011

Both starvation and critical illness are hallmarked by changes in circulating thyroid hormone parameters with typically low T3 concentrations in the absence of elevated TSH. This constellation is labeled nonthyroidal illness (NTI). Because critical illness is often accompanied by anorexia and a failing gastrointestinal tract, the NTI of critical illness may be confounded by nutrient deficiency. In an experimental study performed in a rabbit model, we investigated the impact of nutritional deficit on the NTI of sustained critical illness. Critically ill rabbits were randomly allocated to parenteral nutrition (moderate dose 270 kcal/d) initiated on the day after injury and continued until d 7 of illness or to infusing a similar volume of dextrose 1.4% (14 kcal/d). With early parenteral nutrition during illness, the decrease in serum T3 observed with fasting was reversed, whereas the fall in T4 was not significantly affected. The rise in T3 with parenteral nutrition paralleled an increase of liver and kidney type-1 and a decrease of liver and kidney type-3 deiodinase activity and an increase in circulating and central leptin. Nuclear staining of constitutive androstane receptor and its downstream expression of sulfotransferases were reduced in fasting ill animals. TRH expression in the hypothalamus was not different in fasted and fed ill rabbits, although circulating TSH levels were higher with feeding. In conclusion, in this rabbit model of sustained critical illness, reduced circulating T3, but not T4, levels could be prevented by parenteral nutrition, which may be mediated by leptin and its actions on tissue deiodinase activity.
Minireview: Glucagon in the Pathogenesis of Hypoglycemia and Hyperglycemia in Diabetes
Authors: Cryer Philip E.
Published: December 2011

Pancreatic islet α-cell glucagon secretion is critically dependent on pancreatic islet β-cell insulin secretion. Normally, a decrease in the plasma glucose concentration causes a decrease in β-cell insulin secretion that signals an increase in α-cell glucagon secretion during hypoglycemia. In contrast, an increase in the plasma glucose concentration, among other stimuli, causes an increase in β-cell insulin secretion that signals a decrease, or at least no change, in α-cell glucagon secretion after a meal. In absolute endogenous insulin deficiency (i.e. in type 1 diabetes and in advanced type 2 diabetes), however, β-cell failure results in no decrease in β-cell insulin secretion and thus no increase in α-cell glucagon secretion during hypoglycemia and no increase in β-cell insulin secretion and thus an increase in α-cell glucagon secretion after a meal. In type 1 diabetes and advanced type 2 diabetes, the absence of an increment in glucagon secretion, in the setting of an absent decrement in insulin secretion and an attenuated increment in sympathoadrenal activity, in response to falling plasma glucose concentrations plays a key role in the pathogenesis of iatrogenic hypoglycemia. In addition, there is increasing evidence that, in the aggregate, suggests that relative hyperglucagonemia, in the setting of deficient insulin secretion, plays a role in the pathogenesis of hyperglycemia in diabetes. If so, abnormal glucagon secretion is involved in the pathogenesis of both hypoglycemia and hyperglycemia in diabetes.
Rapid Estrogen Receptor-Mediated Mechanisms Determine the Sexually Dimorphic Sensitivity of Ventricular Myocytes to 17β-Estradiol and the Environmental Endocrine Disruptor Bisphenol A
Authors: Belcher Scott M. , Chen Yamei , Yan Sujuan , Wang Hong-Sheng
Published: December 2011

Previously we showed that 17β-estradiol (E2) and/or the xenoestrogen bisphenol A (BPA) alter ventricular myocyte Ca2+ handing, resulting in increased cardiac arrhythmias in a female-specific manner. In the present study, the roles of estrogen receptors (ER) in mediating the rapid contractile and arrhythmogenic effects of estrogens were examined. Contractility was used as an index to assess the impact of E2 or BPA on Ca2+ handling in rodent ventricular myocytes. The concentration-response curve for the stimulatory effects of BPA and E2 on female myocyte was inverted-U shaped. Detectable effects for each compound were observed at 10−12m, and the most efficacious concentrations for each were at 10−9m. Sensitivity to E2 and BPA was not observed in male myocytes and was abolished in myocytes from ovariectomized females. Analysis using protein-conjugated E2 suggests that these rapid actions are induced by membrane-associated receptors. Analysis using selective ER agonists and antagonists and a genetic ERβ knockout mouse model showed that ERα and ERβ have opposing actions in myocytes and that the balance between ERβ and ERα signaling is the prime regulator of the sex-specific sensitivity toward estrogens. The response of female myocytes to E2 and BPA is dominated by the stimulatory ERβ-mediated signaling, and the absence of BPA and E2 responsiveness in males is due to a counterbalancing-suppressive action of ERα. We conclude that the sex-specific sensitivity of myocytes to estrogens and the rapid arrhythmogenic effects of BPA and estradiol in the female heart are regulated by the balance between ERα and ERβ signaling.
Taperin (c9orf75), a mutated gene in nonsyndromic deafness, encodes a vertebrate specific, nuclear localized protein phosphatase one alpha (PP1α) docking protein
Authors: Ferrar Tony , Chamousset Delphine , De Wever Veerle , Nimick Mhairi , Andersen Jens , Trinkle-Mulcahy Laura , Moorhead Greg B. G.
Published: December 2011

The promiscuous activity of protein phosphatase one (PP1) is controlled in the cell by associated proteins termed regulatory or targeting subunits. Using biochemical and proteomic approaches we demonstrate that the autosomal recessive nonsyndromic hearing loss gene, taperin (C9orf75), encodes a protein that preferentially docks the alpha isoform of PP1. Taperin associates with PP1 through a classic ‘RVxF’ motif and suppresses the general phosphatase activity of the enzyme. The steady-state localization of taperin is predominantly nuclear, however we demonstrate here that the protein can shuttle between the nucleus and cytoplasm and that it is found complexed to PP1 in both of these cellular compartments. Although originally identified as a hearing loss gene, Western blot analyses with taperin-specific antibodies revealed that the protein is widely expressed across mammalian tissues as multiple splice variants. Taperin is a recent proteome addition appearing during the vertebrate lineage with the PP1 binding site embedded within the most conserved region of the protein. Taperin also shares an ancestral relationship with the cytosolic actin binding protein phostensin, another PP1 interacting partner. Quantitative Stable Isotope Labeling by Amino acids in Culture (SILAC)-based mass spectrometry was employed to uncover additional taperin binding partners, and revealed an interaction with the DNA damage response proteins Ku70, Ku80, PARP and topoisomerases I and IIα. Consistent with this, we demonstrate the active recruitment of taperin to sites of DNA damage. This makes taperin a new addition to the family of PP1 targeting subunits involved in the DNA damage repair pathway.
Contracts, Extracontractual Incentives, and Ex Post Behavior in Franchise Channel Relationships
Authors: Kashyap Vishal , Antia Kersi D. , Frazier Gary L.
Published: December 2011

Grounded in agency theory, this study examines how franchisors' ex ante contracts and extracontractual incentives influence their ex post monitoring and enforcement efforts and how combinations of the ex post governance mechanisms drive franchisee behavior. Integrating three archival data sources and a survey of 206 franchisees across eight automotive brands, the authors find that franchisor reliance on contractual completeness appears to result in reduced ex post behavior monitoring and enforcement efforts, while contractual one-sidedness is associated with higher levels of behavior monitoring but reduced enforcement. Extracontractual incentives, when offered to the franchisee, are associated with increases in monitoring and enforcement. In isolation, franchisor monitoring and enforcement efforts are ineffective in eliciting desired franchisee behaviors. However, different combinations of franchisor monitoring and enforcement efforts affect franchisee compliance and opportunism, sometimes with counterproductive results. The study provides an initial baseline of understanding on how ex ante governance characteristics and combinations of ex post governance mechanisms function to facilitate or deter franchisee compliance and opportunism.
Intrinsic Reference Frames of Superior Colliculus Visuomotor Receptive Fields during Head-Unrestrained Gaze Shifts
Authors: DeSouza Joseph F. X. , Keith Gerald P. , Yan Xiaogang , Blohm Gunnar , Wang Hongying , Crawford J. Douglas
Published: December 2011

A sensorimotor neuron's receptive field and its frame of reference are easily conflated within the natural variability of spatial behavior. Here, we capitalized on such natural variations in 3-D eye and head positions during head-unrestrained gaze shifts to visual targets in two monkeys: to determine whether intermediate/deep layer superior colliculus (SC) receptive fields code visual targets or gaze kinematics, within four different frames of reference. Visuomotor receptive fields were either characterized during gaze shifts to visual targets from a central fixation position (32 U) or were partially characterized from each of three initial fixation points (31 U). Natural variations of initial 3-D gaze and head orientation (including torsion) provided spatial separation between four different coordinate frame models (space, head, eye, fixed-vector relative to fixation), whereas natural saccade errors provided spatial separation between target and gaze positions. Using a new statistical method based on predictive sum-of-squares, we found that in our population of 63 neurons (1) receptive field fits to target positions were significantly better than fits to actual gaze shift locations and (2) eye-centered models gave significantly better fits than the head or space frame. An intermediate frames analysis confirmed that individual neuron fits were distributed target-in-eye coordinates. Gaze position “gain” effects with the spatial tuning required for a 3-D reference frame transformation were significant in 23% (7/31) of neurons tested. We conclude that the SC primarily represents gaze targets relative to the eye but also carries early signatures of the 3-D sensorimotor transformation.
Oscillatory Sensory Selection Mechanisms during Intersensory Attention to Rhythmic Auditory and Visual Inputs: A Human Electrocorticographic Investigation
Authors: Gomez-Ramirez Manuel , Kelly Simon P. , Molholm Sophie , Sehatpour Pejman , Schwartz Theodore H. , Foxe John J.
Published: December 2011

Oscillatory entrainment mechanisms are invoked during attentional processing of rhythmically occurring stimuli, whereby their phase alignment regulates the excitability state of neurons coding for anticipated inputs. These mechanisms have been examined in the delta band (1–3 Hz), where entrainment frequency matches the stimulation rate. Here, we investigated entrainment for subdelta rhythmic stimulation, recording from intracranial electrodes over human auditory cortex during an intersensory audiovisual task. Audiovisual stimuli were presented at 0.67 Hz while participants detected targets within one sensory stream and ignored the other. It was found that entrainment operated at twice the stimulation rate (1.33 Hz), and this was reflected by higher amplitude values in the FFT spectrum, cyclic modulation of alpha-amplitude, and phase–amplitude coupling between delta phase and alpha power. In addition, we found that alpha-amplitude was relatively increased in auditory cortex coincident with to-be-ignored auditory stimuli during attention to vision. Thus, the data suggest that entrainment mechanisms operate within a delimited passband such that for subdelta task rhythms, oscillatory harmonics are invoked. The phase of these delta-entrained oscillations modulates alpha-band power. This may in turn increase or decrease responsiveness to relevant and irrelevant stimuli, respectively.
Periodic Organization of a Major Subtype of Pyramidal Neurons in Neocortical Layer V
Authors: Maruoka Hisato , Kubota Kazumasa , Kurokawa Rumi , Tsuruno Shun , Hosoya Toshihiko
Published: December 2011

A major question in neocortical research is the extent to which neuronal organization is stereotyped. Previous studies have revealed functional clustering and neuronal interactions among cortical neurons located within tens of micrometers in the tangential orientation (orientation parallel to the pial surface). In the tangential orientation at this scale, however, it is unknown whether the distribution of neuronal subtypes is random or has any stereotypy. We found that the tangential arrangement of subcerebral projection neurons, which are a major pyramidal neuron subtype in mouse layer V, was not random but significantly periodic. This periodicity, which was observed in multiple cortical areas, had a typical wavelength of 30 μm. Under specific visual stimulation, neurons in single repeating units exhibited strongly correlated c-Fos expression. Therefore, subcerebral projection neurons have a periodic arrangement, and neuronal activity leading to c-Fos expression is similar among neurons in the same repeating units. These results suggest that the neocortex has a periodic functional micro-organization composed of a major neuronal subtype in layer V.
Local Connections of Excitatory Neurons to Corticothalamic Neurons in the Rat Barrel Cortex
Authors: Tanaka Yasuhiro R. , Tanaka Yasuyo H. , Konno Michiteru , Fujiyama Fumino , Sonomura Takahiro , Okamoto-Furuta Keiko , Kameda Hiroshi , Hioki Hiroyuki , Furuta Takahiro , Nakamura Kouichi C. , Kaneko Takeshi
Published: December 2011

Corticothalamic projection neurons in the cerebral cortex constitute an important component of the thalamocortical reciprocal circuit, an essential input/output organization for cortical information processing. However, the spatial organization of local excitatory connections to corticothalamic neurons is only partially understood. In the present study, we first developed an adenovirus vector expressing somatodendritic membrane-targeted green fluorescent protein. After injection of the adenovirus vector into the ventrobasal thalamic complex, a band of layer (L) 6 corticothalamic neurons in the rat barrel cortex were retrogradely labeled. In addition to their cell bodies, fine dendritic spines of corticothalamic neurons were well visualized without the labeling of their axon collaterals or thalamocortical axons. In cortical slices containing retrogradely labeled L6 corticothalamic neurons, we intracellularly stained single pyramidal/spiny neurons of L2–6. We examined the spatial distribution of contact sites between the local axon collaterals of each pyramidal neuron and the dendrites of corticothalamic neurons. We found that corticothalamic neurons received strong and focused connections from L4 neurons just above them, and that the most numerous nearby and distant sources of local excitatory connections to corticothalamic neurons were corticothalamic neurons themselves and L6 putative corticocortical neurons, respectively. These results suggest that L4 neurons may serve as an important source of local excitatory inputs in shaping the cortical modulation of thalamic activity.
Constitutive Upregulation of Chaperone-Mediated Autophagy in Huntington's Disease
Authors: Koga Hiroshi , Martinez-Vicente Marta , Arias Esperanza , Kaushik Susmita , Sulzer David , Cuervo Ana Maria
Published: December 2011

Autophagy contributes to the removal of prone-to-aggregate proteins, but in several instances these pathogenic proteins have been shown to interfere with autophagic activity. In the case of Huntington's disease (HD), a congenital neurodegenerative disorder resulting from mutation in the huntingtin protein, we have previously described that the mutant protein interferes with the ability of autophagic vacuoles to recognize cytosolic cargo. Growing evidence supports the existence of cross talk among autophagic pathways, suggesting the possibility of functional compensation when one of them is compromised. In this study, we have identified a compensatory upregulation of chaperone-mediated autophagy (CMA) in different cellular and mouse models of HD. Components of CMA, namely the lysosome-associated membrane protein type 2A (LAMP-2A) and lysosomal-hsc70, are markedly increased in HD models. The increase in LAMP-2A is achieved through both an increase in the stability of this protein at the lysosomal membrane and transcriptional upregulation of this splice variant of thelamp-2gene. We propose that CMA activity increases in response to macroautophagic dysfunction in the early stages of HD, but that the efficiency of this compensatory mechanism may decrease with age and so contribute to cellular failure and the onset of pathological manifestations.
Saccades during Object Viewing Modulate Oscillatory Phase in the Superior Temporal Sulcus
Authors: Bartlett Adrian M. , Ovaysikia Shima , Logothetis Nikos K. , Hoffman Kari L.
Published: December 2011

Saccadic eye movements (SEMs) are the primary means of gating visual information in primates and strongly influence visual perception. The active exploration of the visual environment (“active vision”) via SEMs produces suppression during saccades and enhancement afterward (i.e., during fixation) in occipital visual areas. In lateral temporal lobe visual areas, the influence, if any, of eye movements is less well understood, despite the necessity of these areas for forming coherent percepts of objects. The upper bank of the superior temporal sulcus (uSTS) is one such area whose sensitivity to SEMs is unknown. We therefore examined how saccades modulate local field potentials (LFPs) in the uSTS of macaque monkeys while they viewed face and nonface object stimuli. LFP phase concentration increased following fixation onset in the alpha (8–14 Hz), beta (14–30 Hz), and gamma (30–60 Hz) bands and was distinct from the image-evoked response. Furthermore, near-coincident onsets of fixation and image presentation—like those occurring in active vision—led to enhanced responses through greater phase concentration in the same frequency bands. Finally, single-unit activity was modulated by the phase of alpha, beta, and gamma oscillations, suggesting that the observed phase-locking influences spike timing in uSTS. Previous research implicates phase concentration in these frequency bands as a correlate of perceptual performance (Womelsdorf et al., 2006; Bosman et al., 2009). Together, these results demonstrate sensitivity to eye movements in an object-processing region of the brain and represent a plausible neural basis for the enhancement of object processing during active vision.
Vesicular Zinc Regulates the Ca2+Sensitivity of a Subpopulation of Presynaptic Vesicles at Hippocampal Mossy Fiber Terminals
Authors: Lavoie Nathalie , Jeyaraju Danny V. , Peralta Modesto R. , Seress László , Pellegrini Luca , Tóth Katalin
Published: December 2011

Synaptic vesicles segregate into functionally diverse subpopulations within presynaptic terminals, yet there is no information about how this may occur. Here we demonstrate that a distinct subgroup of vesicles within individual glutamatergic, mossy fiber terminals contain vesicular zinc that is critical for the rapid release of a subgroup of synaptic vesicles during increased activity in mice. In particular, vesicular zinc dictates the Ca2+sensitivity of release during high-frequency firing. Intense synaptic activity alters the subcellular distribution of zinc in presynaptic terminals and decreases the number of zinc-containing vesicles. Zinc staining also appears in endosomes, an observation that is consistent with the preferential replenishment of zinc-enriched vesicles by bulk endocytosis. We propose that functionally diverse vesicle pools with unique membrane protein composition support different modes of transmission and are generated via distinct recycling pathways.
Resolvin D2 Is a Potent Endogenous Inhibitor for Transient Receptor Potential Subtype V1/A1, Inflammatory Pain, and Spinal Cord Synaptic Plasticity in Mice: Distinct Roles of Resolvin D1, D2, and E1
Authors: Park Chul-Kyu , Xu Zhen-Zhong , Liu Tong , Lü Ning , Serhan Charles N. , Ji Ru-Rong
Published: December 2011

Inflammatory pain such as arthritic pain is typically treated with opioids and cyclo-oxygenase-2 inhibitors with well known side effects. Transient receptor potential subtype vanilloid 1 (TRPV1) and TRP ankyryn 1 (TRPA1) contribute importantly to the genesis of inflammatory pain via both peripheral mechanisms (peripheral sensitization) and spinal cord mechanisms (central sensitization). Although these TRP channels have been intensively studied, little is known about their endogenous inhibitors. Recent studies have demonstrated that the endogenous lipid mediators resolvins (RvE1 and RvD1), derived from ω-3 unsaturated fatty acids, are potent inhibitors for inflammatory pain, without noticeable side effects. However, the molecular mechanisms underlying resolvins' distinct analgesic actions in mice are unclear. RvD2 is a novel family member of resolvins. Here we report that RvD2 is a remarkably potent inhibitor of TRPV1 (IC50= 0.1 nm) and TRPA1 (IC50= 2 nm) in primary sensory neurons, whereas RvE1 and RvD1 selectively inhibited TRPV1 (IC50= 1 nm) and TRPA1 (IC50= 9 nm), respectively. Accordingly, RvD2, RvE1, and RvD1 differentially regulated TRPV1 and TRPA1 agonist-elicited acute pain and spinal cord synaptic plasticity [spontaneous EPSC (sEPSC) frequency increase]. RvD2 also abolished inflammation-induced sEPSC increases (frequency and amplitude), without affecting basal synaptic transmission. Intrathecal administration of RvD2 at very low doses (0.01–1 ng) prevented formalin-induced spontaneous pain. Intrathecal RvD2 also reversed adjuvant-induced inflammatory pain without altering baseline pain and motor function. Finally, intrathecal RvD2 reversed C-fiber stimulation-evoked long-term potentiation in the spinal cord. Our findings suggest distinct roles of resolvins in regulating TRP channels and identify RvD2 as a potent endogenous inhibitor for TRPV1/TRPA1 and inflammatory pain.
RPE65 Is Present in Human Green/Red Cones and Promotes Photopigment Regeneration in anIn VitroCone Cell Model
Authors: Tang Peter H. , Buhusi Mona C. , Ma Jian-Xing , Crouch Rosalie K.
Published: December 2011

RPE65 is an abundantly expressed protein within the retinal pigment epithelium (RPE) of the eye that is required for retinoid metabolism to support vision. Its genetic mutations are linked to the congenital disease Leber congenital amaurosis Type 2 (LCA2) characterized by the early onset of central vision loss. Current gene therapy trials have targeted restoration of functional RPE65 within the RPE of these patients with some success. Recent data show that RPE65 is also present within mouse cones to promote function. In this study, we evaluated the presence of RPE65 in human cones and investigated its potential mechanism for supporting cone function in the 661W cone cell line. We found that RPE65 was selectively expressed in human green/red cones but absent from blue cones and mediated ester hydrolysis for photopigment synthesisin vitro. These data suggest that cone RPE65 supports human diurnal vision, potentially enhancing our strategies for treating LCA2.
cAMP Response Element-Binding Protein Is a Primary Hub of Activity-Driven Neuronal Gene Expression
Authors: Benito Eva , Valor Luis M. , Jimenez-Minchan Maria , Huber Wolfgang , Barco Angel
Published: December 2011

Long-lasting forms of neuronal plasticity requirede novogene expression, but relatively little is known about the events that occur genome-wide in response to activity in a neuronal network. Here, we unveil the gene expression programs initiated in mouse hippocampal neurons in response to different stimuli and explore the contribution of four prominent plasticity-related transcription factors (CREB, SRF, EGR1, and FOS) to these programs. Our study provides a comprehensive view of the intricate genetic networks and interactions elicited by neuronal stimulation identifying hundreds of novel downstream targets, including novel stimulus-associated miRNAs and candidate genes that may be differentially regulated at the exon/promoter level. Our analyses indicate that these four transcription factors impinge on similar biological processes through primarily non-overlapping gene-expression programs. Meta-analysis of the datasets generated in our study and comparison with publicly available transcriptomics data revealed the individual and collective contribution of these transcription factors to different activity-driven genetic programs. In addition, both gain- and loss-of-function experiments support a pivotal role for CREB in membrane-to-nucleus signal transduction in neurons. Our data provide a novel resource for researchers wanting to explore the genetic pathways associated with activity-regulated neuronal functions.
Induction of Activity-Dependent LTD Requires Muscarinic Receptor Activation in Medial Prefrontal Cortex
Authors: Caruana Douglas A. , Warburton E. Clea , Bashir Zafar I.
Published: December 2011

The medial prefrontal cortex (mPFC) forms part of a neural circuit involved in the formation of lasting associations between objects and places. Cholinergic inputs from the basal forebrain innervate the mPFC and may modulate synaptic processes required for the formation of object-in-place memories. To investigate whether acetylcholine regulates synaptic function in the rat mPFC, whole-cell voltage-clamp recordings were made from pyramidal neurons in layer V. Bath application of the cholinergic agonist carbachol caused a potent and long-term depression (LTD) of synaptic responses that was blocked by the muscarinic receptor antagonist scopolamine and was mimicked, in part, by the M1receptor agonists McN-A-343 or AF102B. Furthermore, inhibition of PKC blocked carbachol-mediated LTD. We next determined the requirements for activity-dependent LTD in the prefrontal cortex. Synaptic stimulation that was subthreshold for producing LTD did, however, result in LTD when acetylcholine levels were enhanced by inhibition of acetylcholinesterase or when delivered in the presence of the M1-selective positive allosteric modulator BQCA. Increasing the levels of synaptic stimulation resulted in M1receptor-dependent LTD without the need for pharmacological manipulation of acetylcholine levels. These results show that synaptic stimulation of muscarinic receptors alone can be critical for plastic changes in excitatory synaptic transmission in the mPFC. In turn, these muscarinic mediated events may be important in the formation of object-in-place memories. A loss of basal forebrain cholinergic neurons is a classic hallmark of Alzheimer's dementia and our results provide a potential explanation for the loss of memory associated with the disease.
Hypoxia-Induced Neonatal Seizures Diminish Silent Synapses and Long-Term Potentiation in Hippocampal CA1 Neurons
Authors: Zhou Chengwen , Lippman Bell Jocelyn J. , Sun Hongyu , Jensen Frances E.
Published: December 2011

Neonatal seizures can lead to epilepsy and long-term cognitive deficits into adulthood. Using a rodent model of the most common form of human neonatal seizures, hypoxia-induced seizures (HS), we aimed to determine whether these seizures modify long-term potentiation (LTP) and silent NMDAR-only synapses in hippocampal CA1. At 48–72 h after HS, electrophysiology and immunofluorescent confocal microscopy revealed a significant decrease in the incidence of silent synapses, and an increase in AMPARs at the synapses. Coincident with this decrease in silent synapses, there was an attenuation of LTP elicited by either tetanic stimulation of Schaffer collaterals or a pairing protocol, and persistent attenuation of LTP in slices removed in later adulthood after P10 HS. Furthermore, postseizure treatmentin vivowith the AMPAR antagonist 2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline (NBQX) protected against the HS-induced depletion of silent synapses and preserved LTP. Thus, this study demonstrates a novel mechanism by which early life seizures could impair synaptic plasticity, suggesting a potential target for therapeutic strategies to prevent long-term cognitive deficits.
Gas-Temperature Imaging in a Microwave-Plasma Nanoparticle-Synthesis Reactor Using Multi-Line NO-LIF Thermometry
Authors: Hecht C. , Abdali A. , Dreier T. , Schulz C.
Published: December 2011

Multi-line NO-LIF thermometry is used to determine the two-dimensional temperature distribution inside a low-pressure plasma reactor. The applicability of multi-line temperature measurements to non-equilibrium plasma environments was evaluated. Temperatures between 300 and 3000 K have been observed, while microwave power, and pressure show a strong effect on the temperature distribution. Metal-organic precursors added for particle synthesis additionally influence the temperature through the heat release during particle formation and the oxidation of organic ligands.
Identification of Tetrahydrofuran Reaction Pathways in Premixed Flames
Authors: Kasper Tina , Lucassen Arnas , Jasper Ahren W. , Li Wenjun , Westmoreland Philip R. , Kohse-Höinghaus Katharina , Yang Bin , Wang Juan , Cool Terrill A. , Hansen Nils
Published: December 2011

Premixed low-pressure tetrahydrofuran/oxygen/argon flames are investigated by photoionization molecular-beam mass spectrometry using vacuum-ultraviolet synchrotron radiation. For two equivalence ratios (φ = 1.00 and 1.75), mole fractions are measured as a function of distance from the burner for almost 60 intermediates with molar masses ranging from 2 (H2) to 88 (C4H6O2), providing a broad database for flame modeling studies. The isomeric composition is resolved by comparisons between experimental photoionization efficiency data and theoretical simulations, based on calculated ionization energies and Franck-Condon factors. Special emphasis is put on the resolution of the first reaction steps in the fuel destruction. The photoionization experiments are complemented by electron-ionization molecular-beam mass-spectrometry measurements that provide data with high mass resolution. For three additional flames with intermediate equivalence ratios (φ = 1.20, 1.40 and 1.60), mole fractions of major species and photoionization efficiency spectra of intermediate species are reported, extending the database for the development of chemical kinetic models.
Stroke After Coronary Bypass Surgery Is Mainly Related to Diffuse Atherosclerotic Disease
Authors: Senay Sahin , Toraman Fevzi , Akg�n Yasemin , Aydin Ebuzer , Karabulut Hasan , Alhan Cem , Sarioglu Tayyar
Published: December 2011

Objective: This study aims to investigate the risk factors for postoperative stroke and analysis of outcome after coronary bypass surgery with cardiopulmonary bypass.

Methods: Between 1999 and 2008, 3248 consecutive patients who underwent isolated coronary surgery with cardiopulmonary bypass were prospectively enrolled in the study. Demographic and perioperative data were analyzed. Postoperative stroke was defined as severe adverse neurological events including permanent deficits or cerebral lesions with radiological demonstration of cerebral infarction within the first postoperative month.

Results: In total, 32 patients (0.9%) were determined with stroke. Univariate risk factors for postoperative stroke were determined as preoperative unstable angina (P = .006), Canadian Class of Angina (CCA) ? 3 (P = .001), preoperative creatinin level >1.2 mg/dL (P = .001), left main coronary artery disease (P = .04), chronic obstructive lung disease (P = .04), peripheral arterial disease (P < .001), New York Heart Association (NYHA) Class ? 3 (P = .004), preoperative renal insufficiency (P = .001), age > 65 years (P = .04), preoperative hypothyroidism (P = .02), postoperative low cardiac output state (P < .001), severe coronary artery disease requiring distal anastomosis ? 4 (P = .05), non-elective operation (P = .02), and body mass index ? 25 (P = .02). Multivariate analysis revealed peripheral arterial disease (odds ratio [OR], 5.2; 95% confidence interval [CI], 1.9-14.0; P = .001), severe coronary artery disease (OR, 3.1; 95% CI, 1.1-8.5; P = .02), and postoperative low cardiac output state (OR, 5.1; 95% CI, 1.4-18.2; P = .01) as the independent risk factors.

Conclusions: Stroke after coronary bypass surgery with cardiopulmonary bypass is mainly related to diffuse atherosclerotic disease.
Quantitative Genetics of Genomic Imprinting: A Comparison of Simple Variance Derivations, the Effects of Inbreeding, and Response to Selection
Authors: Santure Anna W , Spencer Hamish G
Published: December 2011

The level of expression of an imprinted gene is dependent on the sex of the parent from which it was inherited. As a result, reciprocal heterozygotes in a population may have different mean phenotypes for quantitative traits. Using standard quantitative genetic methods for deriving breeding values, population variances, and covariances between relatives, we demonstrate that although these approaches are equivalent under Mendelian expression, this equivalence is lost when genomic imprinting is acting. Imprinting introduces both parent-of-origin-dependent and generation-dependent effects that result in differences in the way additive and dominance effects are defined for the various approaches. Further, imprinting creates a covariance between additive and dominance terms absent under Mendelian expression, but the expression for this covariance cannot be derived using a number of the standard approaches for defining additive and dominance terms. Inbreeding also generates such a covariance, and we demonstrate that a modified method for partitioning variances can easily accommodate both inbreeding and imprinting. As with inbreeding, the concept of breeding values has no useful meaning for an imprinted trait. Finally, we derive the expression for the response to selection under imprinting, and conclude that the response to selection for an imprinted trait cannot be predicted from the breeder’s equation, even when there is no dominance.
Genome-Wide Analysis to Identify Pathways Affecting Telomere-Initiated Senescence in Budding Yeast
Authors: Chang Hsin-Yu , Lawless Conor , Addinall Stephen G , Oexle Sarah , Taschuk Morgan , Wipat Anil , Wilkinson Darren J , Lydall David
Published: December 2011

In telomerase-deficient yeast cells, like equivalent mammalian cells, telomeres shorten over many generations until a period of senescence/crisis is reached. After this, a small fraction of cells can escape senescence, principally using recombination-dependent mechanisms. To investigate the pathways that affect entry into and recovery from telomere-driven senescence, we combined a gene deletion disrupting telomerase (est1Δ) with the systematic yeast deletion collection and measured senescence characteristics in high-throughput assays. As expected, the vast majority of gene deletions showed no strong effects on entry into/exit from senescence. However, around 200 gene deletions behaving similarly to a rad52Δest1Δ archetype (rad52Δ affects homologous recombination) accelerated entry into senescence, and such cells often could not recover growth. A smaller number of strains similar to a rif1Δest1Δ archetype (rif1Δ affects proteins that bind telomeres) accelerated entry into senescence but also accelerated recovery from senescence. Our genome-wide analysis identifies genes that affect entry into and/or exit from telomere-initiated senescence and will be of interest to those studying telomere biology, replicative senescence, cancer, and ageing. Our dataset is complementary to other high-throughput studies relevant to telomere biology, genetic stability, and DNA damage responses.
Stacks: Building and Genotyping Loci De Novo From Short-Read Sequences
Authors: Catchen Julian M , Amores Angel , Hohenlohe Paul , Cresko William , Postlethwait John H
Published: December 2011

Advances in sequencing technology provide special opportunities for genotyping individuals with speed and thrift, but the lack of software to automate the calling of tens of thousands of genotypes over hundreds of individuals has hindered progress. Stacks is a software system that uses short-read sequence data to identify and genotype loci in a set of individuals either de novo or by comparison to a reference genome. From reduced representation Illumina sequence data, such as RAD-tags, Stacks can recover thousands of single nucleotide polymorphism (SNP) markers useful for the genetic analysis of crosses or populations. Stacks can generate markers for ultra-dense genetic linkage maps, facilitate the examination of population phylogeography, and help in reference genome assembly. We report here the algorithms implemented in Stacks and demonstrate their efficacy by constructing loci from simulated RAD-tags taken from the stickleback reference genome and by recapitulating and improving a genetic map of the zebrafish, Danio rerio.