bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for Vpr-dependent HIV-1 Replication in Human CD4+CEM.NKR T-Cells
Authors: Zhou Tao , Dang Ying , Baker Jacob J , Zhou Jiajun , Zheng Yong-Hui
Published: November 2012

Background

Vpr is exclusively expressed in primate lentiviruses and contributes to viral replication and disease progression in vivo. HIV-1 Vpr has two major activities in vitro: arrest of cell cycle in the G2 phase (G2 arrest), and enhancement of viral replication in macrophages. Previously, we reported a potent HIV-1 restriction in the human CD4+ CEM.NKR (NKR) T cells, where wild-type (WT) HIV-1 replication was inhibited by almost 1,000-fold. From the parental NKR cells, we isolated eight clones by limiting dilution. These clones showed three levels of resistance to the WT HIV-1 infection: non-permissive (NP), semi-permissive (SP), and permissive (P). Here, we compared the replication of WT, Vif-defective, Vpr-defective, and Vpu-defective viruses in these cells.

Results

Although both WT and Vpu-defective viruses could replicate in the permissive and semi-permissive clones, the replication of Vif-defective and Vpr-defective viruses was completely restricted. The expression of APOBEC3G (A3G) cytidine deaminase in NKR cells explains why Vif, but not Vpr, was required for HIV-1 replication. When the Vpr-defective virus life cycle was compared with the WT virus life cycle in the semi-permissive cells, it was found that the Vpr-defective virus could enter the cell and produce virions containing properly processed Gag and Env proteins, but these virions showed much less efficiency for reverse transcription during the next-round of infection. In addition, although viral replication was restricted in the non-permissive cells, treatment with arsenic trioxide (As2O3) could completely restore WT, but not Vpr-defective virus replication. Moreover, disruption of Vpr binding to its cofactor DCAF1 and/or induction of G2 arrest activity did not disrupt the Vpr activity in enhancing HIV-1 replication in NKR cells.

Conclusions

These results demonstrate that HIV-1 replication in NKR cells is Vpr-dependent. Vpr promotes HIV-1 replication from the 2nd cycle likely by overcoming a block at early stage of viral replication; and this activity does not require DCAF1 and G2 arrest. Further studies of this mechanism should provide new understanding of Vpr function in the HIV-1 life cycle.
Effectiveness of an antimicrobial treatment scheme in a confined glanders outbreak
Authors: Saqib Muhammad , Muhammad Ghulam , Naureen Abeera , Hussain Muhammad H , Asi M Nadeem , Mansoor M Khalid , Toufeer Mehdi , Khan Iahtasham , Neubauer Heinrich , Sprague Lisa D
Published: November 2012

Background

Glanders is a contagious and fatal zoonotic disease of solipeds caused by the Gram-negative bacterium Burkholderia (B.) mallei. Although regulations call for culling of diseased animals, certain situations e.g. wild life conservation, highly valuable breeding stock, could benefit from effective treatment schemes and post-exposure prophylaxis.

Results

Twenty three culture positive glanderous horses were successfully treated during a confined outbreak by applying a treatment protocol of 12 weeks duration based on the parenteral administration of enrofloxacin and trimethoprim plus sulfadiazine, followed by the oral administration of doxycycline. Induction of immunosupression in six randomly chosen horses after completion of treatment did not lead to recrudescence of disease.

Conclusion

This study demonstrates that long term treatment of glanderous horses with a combination of various antibiotics seems to eliminate the agent from the organism. However, more studies are needed to test the effectiveness of this treatment regime on B. mallei strains from different endemic regions. Due to its cost and duration, this treatment can only be an option in certain situations and should not replace the current “testing and culling” policy, in conjunction with adequate compensation to prevent spreading of disease.
Effects of multiple conformers per compound upon 3-D similarity search and bioassay data analysis
Authors: Kim Sunghwan , Bolton Evan E , Bryant Stephen H
Published: November 2012

Background

To improve the utility of PubChem, a public repository containing biological activities of small molecules, the PubChem3D project adds computationally-derived three-dimensional (3-D) descriptions to the small-molecule records contained in the PubChem Compound database and provides various search and analysis tools that exploit 3-D molecular similarity. Therefore, the efficient use of PubChem3D resources requires an understanding of the statistical and biological meaning of computed 3-D molecular similarity scores between molecules.

Results

The present study investigated effects of employing multiple conformers per compound upon the 3-D similarity scores between ten thousand randomly selected biologically-tested compounds (10-K set) and between non-inactive compounds in a given biological assay (156-K set). When the “best-conformer-pair” approach, in which a 3-D similarity score between two compounds is represented by the greatest similarity score among all possible conformer pairs arising from a compound pair, was employed with ten diverse conformers per compound, the average 3-D similarity scores for the 10-K set increased by 0.11, 0.09, 0.15, 0.16, 0.07, and 0.18 for ST

ST-opt
, CT

ST-opt
, ComboT

ST-opt
, ST

CT-opt
, CT

CT-opt
, and ComboT

CT-opt
, respectively, relative to the corresponding averages computed using a single conformer per compound. Interestingly, the best-conformer-pair approach also increased the average 3-D similarity scores for the non-inactive–non-inactive (NN) pairs for a given assay, by comparable amounts to those for the random compound pairs, although some assays showed a pronounced increase in the per-assay NN-pair 3-D similarity scores, compared to the average increase for the random compound pairs.

Conclusion

These results suggest that the use of ten diverse conformers per compound in PubChem bioassay data analysis using 3-D molecular similarity is not expected to increase the separation of non-inactive from random and inactive spaces “on average”, although some assays show a noticeable separation between the non-inactive and random spaces when multiple conformers are used for each compound. The present study is a critical next step to understand effects of conformational diversity of the molecules upon the 3-D molecular similarity and its application to biological activity data analysis in PubChem. The results of this study may be helpful to build search and analysis tools that exploit 3-D molecular similarity between compounds archived in PubChem and other molecular libraries in a more efficient way.
TNF/TNFR signal transduction pathway-mediated anti-apoptosis and anti-inflammatory effects of sodium ferulate on IL-1β-induced rat osteoarthritis chondrocytes in vitro
Authors: Qin Jun , Shang Liang , Ping An-song , Li Jing , Li Xiao-jun , Yu Hong , Magdalou Jacques , Chen Liao-bin , Wang Hui
Published: November 2012

Introduction

Sodium ferulate (SF) is a natural component of traditional Chinese herbs. Our previous study shows that SF has a protective effect on osteoarthritis (OA). The objective of this study was to investigate the effect of SF on the TNF/TNF receptor (TNFR) signal transduction pathway of rat OA chondrocytes.

Methods

Primary rat articular chondrocytes were co-treated with IL-1β and SF. Chondrocyte apoptosis was assessed by fluorescein isothiocyanate-annexin V/propidium iodide assay. The PCR array was used to screen the expression of 84 key genes involved in apoptosis. The release of TNFα and prostaglandin E2 were analyzed by ELISA. Expressions of proteins were assessed by western blotting. The activity of NF-κB was determined by electrophoretic mobility shift assay (EMSA). Gene expression of inducible nitric oxide synthase (iNOS) was evaluated by real-time quantitative PCR. The nitric oxide content was measured with the Griess method.

Results

After treatment with SF, the apoptosis rate of chondrocytes significantly attenuated (P < 0.01). Results of the apoptosis PCR array suggested that mRNA expression of some core proteins in the TNF/TNFR pathway showed valuable regulation. The protein expressions of TNFα, TNFR-1, TNF receptor-associated death domain, caspase-8 and caspase-3 were prevented by SF in a concentration-dependent manner. SF also inhibited activities of caspase-8 and caspase-3 compared with the OA model control (P < 0.01). TNF receptor-associated factor-2 expression, phosphorylations of inhibitor of NF-κB kinase (IKK) subunits alpha and beta, and NF-κB inhibitor, alpha (IκBα) were all concentration-dependently suppressed by SF treatment. The results of EMSA showed that SF inhibited the activity of NF-κB. In addition, the expressions of cycloxygenase-2 and iNOS and the contents of prostaglandin E2 and NO were attenuated with the treatment of SF (P < 0.01).

Conclusion

SF has anti-apoptosis and anti-inflammatory effects on an OA model induced by IL-1β in vitro, which were due to inhibitory actions on the caspase-dependent apoptosis pathway and the IKK/NF-κB signal transduction pathway of the TNF/TNFR pathway.
Microsomal triacylglycerol transfer protein (MTP) is required to expand tracheal lumen in Drosophila in a cell-autonomous manner
Authors: Baer Magdalena M. , Palm Wilhelm , Eaton Suzanne , Leptin Maria , Affolter Markus
Published: November 2012

The Drosophila tracheal system is a useful model for dissecting the molecular mechanisms controlling the assembly and expansion of tubular organs. We have identified microsomal triacylglycerol transfer protein (MTP) as a new player involved in the lumen expansion in unicellular tubes. MTP is an endoplasmic reticulum resident protein that can transfer triglycerides and phospholipids between membranes in vitro. MTP lipid transfer activity is crucial for the assembly and secretion of apoB family lipoproteins, which are carriers of lipids between different tissues. Here we describe an unexpected role of MTP in tracheal development, which we postulate to be independent of its known function in lipoprotein secretion. We propose that, in tracheal cells, MTP is involved in regulation of de novo apical membrane delivery to the existing lumen and thus promotes proper expansion of the larval tracheal system.
Cell cycle regulation by the NEK family of protein kinases
Authors: Fry Andrew M. , O'Regan Laura , Sabir Sarah R. , Bayliss Richard
Published: November 2012

Genetic screens for cell division cycle mutants in the filamentous fungus Aspergillus nidulans led to the discovery of never-in-mitosis A (NIMA), a serine/threonine kinase that is required for mitotic entry. Since that discovery, NIMA-related kinases, or NEKs, have been identified in most eukaryotes, including humans where eleven genetically distinct proteins named NEK1 to NEK11 are expressed. Although there is no evidence that human NEKs are essential for mitotic entry, it is clear that several NEK family members have important roles in cell cycle control. In particular, NEK2, NEK6, NEK7 and NEK9 contribute to the establishment of the microtubule-based mitotic spindle, whereas NEK1, NEK10 and NEK11 have been implicated in the DNA damage response. Roles for NEKs in other aspects of mitotic progression, such as chromatin condensation, nuclear envelope breakdown, spindle assembly checkpoint signalling and cytokinesis have also been proposed. Interestingly, NEK1 and NEK8 also function within cilia, the microtubule-based structures that are nucleated from basal bodies. This has led to the current hypothesis that NEKs have evolved to coordinate microtubule-dependent processes in both dividing and non-dividing cells. Here, we review the functions of the human NEKs, with particular emphasis on those family members that are involved in cell cycle control, and consider their potential as therapeutic targets in cancer.
Beyond the Jamming Avoidance Response: weakly electric fish respond to the envelope of social electrosensory signals
Authors: Stamper Sarah A. , Madhav Manu S. , Cowan Noah J. , Fortune Eric S.
Published: November 2012

Recent studies have shown that central nervous system neurons in weakly electric fish respond to artificially constructed electrosensory envelopes, but the behavioral relevance of such stimuli is unclear. Here we investigate the possibility that social context creates envelopes that drive behavior. When Eigenmannia virescens are in groups of three or more, the interactions between their pseudo-sinusoidal electric fields can generate ‘social envelopes’. We developed a simple mathematical prediction for how fish might respond to such social envelopes. To test this prediction, we measured the responses of E. virescens to stimuli consisting of two sinusoids, each outside the range of the Jamming Avoidance Response (JAR), that when added to the fish's own electric field produced low-frequency (below 10 Hz) social envelopes. Fish changed their electric organ discharge (EOD) frequency in response to these envelopes, which we have termed the Social Envelope Response (SER). In 99% of trials, the direction of the SER was consistent with the mathematical prediction. The SER was strongest in response to the lowest initial envelope frequency tested (2 Hz) and depended on stimulus amplitude. The SER generally resulted in an increase of the envelope frequency during the course of a trial, suggesting that this behavior may be a mechanism for avoiding low-frequency social envelopes. Importantly, the direction of the SER was not predicted by the superposition of two JAR responses: the SER was insensitive to the amplitude ratio between the sinusoids used to generate the envelope, but was instead predicted by the sign of the difference of difference frequencies.
Structures and processes for priority-setting by health-care funders: a national survey of primary care trusts in England
Authors: Robinson Suzanne , Dickinson Helen , Freeman Tim , Rumbold Benedict , Williams Iestyn
Published: November 2012

Although explicit priority-setting is advocated in the health services literature and supported by the policies of many governments, relatively little is known about the extent and ways in which this is carried out at local decision-making levels. Our objective was to undertake a survey of local resource allocaters in the English National Health Services in order to map and explore current priority-setting activity. A national survey was sent to Directors of Commissioning in English Primary Care Trusts (PCTs). The survey was designed to provide a picture of the types of priority-setting activities and techniques that are in place and offer some assessment of their perceived effectiveness. There is variation in the scale, aims and methods of priority-setting functions across PCTs. A perceived strength of priority-setting processes is in relation to the use of particular tools and/or development of formal processes that are felt to increase transparency. Perceived weaknesses tended to lie in the inability to sufficiently engage with a range of stakeholders. Although a number of formal priority-setting processes have been developed, there are a series of remaining challenges such as ensuring priority-setting goes beyond the margins and is embedded in budget management, and the development of disinvestment as well as investment strategies. Furthermore, if we are genuinely interested in a more explicit approach to priority-setting, then fostering a more inclusive and transparent process will be required.
Comparing the validity of different measures of illness severity: a hospital-level analysis for acute myocardial infarction
Authors: Gandjour Afschin , Ku-Goto Meei-Hsiang , Ho Vivian
Published: November 2012

The aim of the study is to assess the validity of three measures of illness severity (prior year's hospital expenditures, Charlson and Elixhauser indices), by analysing the effect of introducing report cards on hospitals treating patients with acute myocardial infarction (AMI). Medicare claims data were obtained for 1992–1997 for AMI patients aged 65+. We used differences-in-differences regression analysis to assess the impact of report cards introduced in New Jersey and Pennsylvania on the illness severity of AMI patients with and without coronary artery bypass graft (CABG) surgery (relative to states without report cards). The analysis was conducted at the hospital level. For validation we used raw mortality and re-admission trends for AMI patients.

While prior hospital expenditures suggest a considerable change in the illness severity of AMI patients in Pennsylvania relative to other states, raw mortality and re-admission trends in Pennsylvania are relatively consistent with the trend in the rest of the USA. In line with raw mortality and re-admission data, the Charlson and Elixhauser indices do not imply a considerable change in the severity of AMI patients in Pennsylvania. For CABG patients, illness severity – as measured by all three severity measurement methods – decreased after introduction of report cards, particularly in Pennsylvania. In conclusion, for AMI patients the Charlson and Elixhauser indices are a more valid measure of illness severity than prior year's hospital expenditures. After report cards were introduced, healthier AMI patients were more likely to receive CABG surgery, while sicker patients were avoided.
Destructive rib lesions in an HIV sero-negative male: an unusual presentation of tuberculosis in a high tuberculosis prevalence setting
Authors: Nakiyingi Lydia , Bwanika John M , Lukande Robert , Kirenga Bruce , Mwambu Tom P , Worodria William , Okot-Nwang Martin
Published: November 2012

Tuberculosis (TB) of the rib is a very rare form of skeletal TB and its diagnosis may be difficult because of a low index of suspicion by clinicians. The presentation often mimics malignant disease clinically and radiologically and diagnosis may only be confirmed by tissue biopsy. We present a 32-year-old HIV-negative man who presented with a three-month history of progressively worsening pleuritic chest pain, weight loss, fatigue, anorexia and low-grade fever with night sweats. A chest computerized tomography (CT) scan showed destructive lesions in the right fourth and seventh ribs with no pulmonary lesions. A diagnosis of TB of the rib was made after surgical resection and histopathology of the affected tissue. There was significant improvement when anti-TB therapy was initiated. This case report emphasizes the importance of a high index of suspicion of TB in patients presenting with destructive bone lesions in regions with high prevalence of TB.
Action Potential-Independent and Pharmacologically Unique Vesicular Serotonin Release from Dendrites
Authors: Colgan Lesley A. , Cavolo Samantha L. , Commons Kathryn G. , Levitan Edwin S.
Published: November 2012

Serotonin released within the dorsal raphe nucleus (DR) induces feedback inhibition of serotonin neuron activity and consequently regulates mood-controlling serotonin release throughout the forebrain. Serotonin packaged in vesicles is released in response to action potentials by the serotonin neuron soma and terminals, but the potential for release by dendrites is unknown. Here, three-photon microscopy imaging of endogenous serotonin in living rat brain slice, immunofluorescence, and immunogold electron microscopy detection of VMAT2 (vesicular monoamine transporter 2) establish the presence of vesicular serotonin within DR dendrites. Furthermore, activation of glutamate receptors is shown to induce vesicular serotonin release from dendrites. However, unlike release from the soma and terminals, dendritic serotonin release is independent of action potentials, relies on L-type Ca2+channels, is induced preferentially by NMDA, and displays distinct sensitivity to the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine. The unique control of dendritic serotonin release has important implications for DR physiology and the antidepressant action of SSRIs, dihydropyridines, and NMDA receptor antagonists.
Ectopic Vesicular Glutamate Release at the Optic Nerve Head and Axon Loss in Mouse Experimental Glaucoma
Authors: Fu Christine T. , Sretavan David W.
Published: November 2012

Although clinical and experimental observations indicate that the optic nerve head (ONH) is a major site of axon degeneration in glaucoma, the mechanisms by which local retinal ganglion cell (RGC) axons are injured and damage spreads among axons remain poorly defined. Using a laser-induced ocular hypertension (LIOH) mouse model of glaucoma, we found that within 48 h of intraocular pressure elevation, RGC axon segments within the ONH exhibited ectopic accumulation and colocalization of multiple components of the glutamatergic presynaptic machinery including the vesicular glutamate transporter VGLUT2, several synaptic vesicle marker proteins, glutamate, the solubleN-ethylmaleimide-sensitive factor attachment protein receptor complex and active zone cytomatrix components, as well as ultrastructurally identified, synaptophysin-containing vesicles. Ectopic vesicle exocytosis and glutamate release were detected in acute preparations of the LIOH ONH. Immunolocalization and analysis using the ionotropic receptor channel-permeant cation agmatine indicated that ONH axon segments and glia expressed glutamate receptors, and these receptors were more active after LIOH compared with controls. Pharmacological antagonism of glutamate receptors and neuronal activity resulted in increased RGC axon sparingin vivo. Furthermore,in vivoRGC-specific genetic disruption of the vesicular glutamate transporter VGLUT2 or the obligatory NMDA receptor subunit NR1 promoted axon survival in experimental glaucoma. As the inhibition of ectopic glutamate vesicular release or glutamate receptivity can independently modify the severity of RGC axon loss, synaptic release mechanisms may provide useful therapeutic entry points into glaucomatous axon degeneration.
Long-Term Stabilization of Place Cell Remapping Produced by a Fearful Experience
Authors: Wang Melissa E. , Wann Ellen G. , Yuan Robin K. , Ramos Álvarez Manuel M. , Stead Squire M. , Muzzio Isabel A.
Published: November 2012

Fear is an emotional response to danger that is highly conserved throughout evolution because it is critical for survival. Accordingly, episodic memory for fearful locations is widely studied using contextual fear conditioning, a hippocampus-dependent task (Kim and Fanselow, 1992; Phillips and LeDoux, 1992). The hippocampus has been implicated in episodic emotional memory and is thought to integrate emotional stimuli within a spatial framework. Physiological evidence supporting the role of the hippocampus in contextual fear indicates that pyramidal cells in this region, which fire in specific locations as an animal moves through an environment, shift their preferred firing locations shortly after the presentation of an aversive stimulus (Moita et al., 2004). However, the long-term physiological mechanisms through which emotional memories are encoded by the hippocampus are unknown. Here we show that during and directly after a fearful experience, new hippocampal representations are established and persist in the long term. We recorded from the same place cells in mouse hippocampal area CA1 over several days during predator odor contextual fear conditioning and found that a subset of cells changed their preferred firing locations in response to the fearful stimulus. Furthermore, the newly formed representations of the fearful context stabilized in the long term. Our results demonstrate that place cells respond to the presence of an aversive stimulus, modify their firing patterns during emotional learning, and stabilize a long-term spatial representation in response to a fearful encounter. The persistent nature of these representations may contribute to the enduring quality of emotional memories.
Modulation of Mouse Rod Response Decay by Rhodopsin Kinase and Recoverin
Authors: Chen Ching-Kang , Woodruff Michael L. , Chen Frank S. , Chen Yenlin , Cilluffo Marianne C. , Tranchina Daniel , Fain Gordon L.
Published: November 2012

Light isomerizes 11-cis-retinal in a retinal rod and produces an active form of rhodopsin (Rh*) that binds to the G-protein transducin and activates the phototransduction cascade. Rh* is turned off by phosphorylation by rhodopsin kinase [G-protein-coupled receptor kinase 1 (GRK1)] and subsequent binding of arrestin. To evaluate the role of GRK1 in rod light response decay, we have generated the transgenic mouseRKS561Lin which GRK1, which is normally present at only 2–3% of rhodopsin, is overexpressed by ∼12-fold. Overexpression of GRK1 increases the rate of Rh* phosphorylation and reduces the exponential decay constant of the response (τREC) and the limiting time constant (τD) both by ∼30%; these decreases are highly significant. Similar decreases are produced inRv−/−rods, in which the GRK1-binding protein recoverin has been genetically deleted. These changes in response decay are produced by acceleration of light-activated phosphodiesterase (PDE*) decay rather than Rh* decay, because light-activated PDE* decay remains rate limiting for response decay in bothRKS561LandRv−/−rods. A model incorporating an effect of GRK1 on light-activated PDE* decay rate can satisfactorily account for the changes in response amplitude and waveform. Modulation of response decay in background light is nearly eliminated by deletion of recoverin. Our experiments indicate that rhodopsin kinase and recoverin, in addition to their well-known role in regulating the turning off of Rh*, can also modulate the decay of light-activated PDE*, and the effects of these proteins on light-activated PDE* decay may be responsible for the quickening of response recovery in background light.
Dynamic and Static Facial Expressions Decoded from Motion-Sensitive Areas in the Macaque Monkey
Authors: Furl Nicholas , Hadj-Bouziane Fadila , Liu Ning , Averbeck Bruno B. , Ungerleider Leslie G.
Published: November 2012

Humans adeptly use visual motion to recognize socially relevant facial information. The macaque provides a model visual system for studying neural coding of expression movements, as its superior temporal sulcus (STS) possesses brain areas selective for faces and areas sensitive to visual motion. We used functional magnetic resonance imaging and facial stimuli to localize motion-sensitive areas [motion in faces (Mf) areas], which responded more to dynamic faces compared with static faces, and face-selective areas, which responded selectively to faces compared with objects and places. Using multivariate analysis, we found that information about both dynamic and static facial expressions could be robustly decoded from Mf areas. By contrast, face-selective areas exhibited relatively less facial expression information. Classifiers trained with expressions from one motion type (dynamic or static) showed poor generalization to the other motion type, suggesting that Mf areas employ separate and nonconfusable neural codes for dynamic and static presentations of the same expressions. We also show that some of the motion sensitivity elicited by facial stimuli was not specific to faces but could also be elicited by moving dots, particularly in fundus of the superior temporal and middle superior temporal polysensory/lower superior temporal areas, confirming their already well established low-level motion sensitivity. A different pattern was found in anterior STS, which responded more to dynamic than to static faces but was not sensitive to dot motion. Overall, we show that emotional expressions are mostly represented outside of face-selective cortex, in areas sensitive to motion. These regions may play a fundamental role in enhancing recognition of facial expression despite the complex stimulus changes associated with motion.
A Strong Constraint to the Joint Processing of Pairs of Cortical Signals
Authors: Ghose Kaushik , Maunsell John H. R.
Published: November 2012

An important question in neuroscience is how the activity from spatially distributed cortical representations is integrated and processed together. In this study, we used a new approach to investigate the integration of distributed cortical activity. We used microstimulation to directly activate pairs of sites in primary visual cortex of rhesus monkeys. The sites were activated either singly or jointly, and the monkeys were trained to behaviorally report detection of the activation of either cortical site. We compared the detection performance with predictions from two different mathematical models of signal combination. Our data show that, at cortical separations <1 mm, signal integration is well described as a linear combination (d′summation) of individual site activity. At larger separations, signal integration is better described as a maximum operation on the site signals. We compare our neurophysiological findings to existing psychophysical data and suggest the intriguing possibility that cortical activity originating at spatial separations greater than ∼1 mm is processed as if by parallel, independent circuits whose signals can be compared against each other but not summed. This in turn implies that there is a strong constraint to the kinds of computations the brain can perform with spatially distributed cortical activity.
Inactivating Anterior Insular Cortex Reduces Risk Taking
Authors: Ishii Hironori , Ohara Shinya , Tobler Philippe N. , Tsutsui Ken-Ichiro , Iijima Toshio
Published: November 2012

We often have to make risky decisions between alternatives with outcomes that can be better or worse than the outcomes of safer alternatives. Although previous studies have implicated various brain regions in risky decision making, it remains unknown which regions are crucial for balancing whether to take a risk or play it safe. Here, we focused on the anterior insular cortex (AIC), the causal involvement of which in risky decision making is still unclear, although human imaging studies have reported AIC activation in various gambling tasks. We investigated the effects of temporarily inactivating the AIC on rats' risk preference in two types of gambling tasks, one in which risk arose in reward amount and one in which it arose in reward delay. As a control within the same subjects, we inactivated the adjacent orbitofrontal cortex (OFC), which is well known to affect risk preference. In both gambling tasks, AIC inactivation decreased risk preference whereas OFC inactivation increased it. In risk-free control situations, AIC and OFC inactivations did not affect decision making. These results suggest that the AIC is causally involved in risky decision making and promotes risk taking. The AIC and OFC may be crucial for the opposing motives of whether to take a risk or avoid it.
Dorsomedial Prefrontal Cortex Mediates Rapid Evaluations Predicting the Outcome of Romantic Interactions
Authors: Cooper Jeffrey C. , Dunne Simon , Furey Teresa , O'Doherty John P.
Published: November 2012

Humans frequently make real-world decisions based on rapid evaluations of minimal information; for example, should we talk to an attractive stranger at a party? Little is known, however, about how the brain makes rapid evaluations with real and immediate social consequences. To address this question, we scanned participants with functional magnetic resonance imaging (fMRI) while they viewed photos of individuals that they subsequently met at real-life “speed-dating” events. Neural activity in two areas of dorsomedial prefrontal cortex (DMPFC), paracingulate cortex, and rostromedial prefrontal cortex (RMPFC) was predictive of whether each individual would be ultimately pursued for a romantic relationship or rejected. Activity in these areas was attributable to two distinct components of romantic evaluation: either consensus judgments about physical beauty (paracingulate cortex) or individualized preferences based on a partner's perceived personality (RMPFC). These data identify novel computational roles for these regions of the DMPFC in even very rapid social evaluations. Even a first glance, then, can accurately predict romantic desire, but that glance involves a mix of physical and psychological judgments that depend on specific regions of DMPFC.
Short-Term Synaptic Plasticity Compensates for Variability in Number of Motor Neurons at a Neuromuscular Junction
Authors: Daur Nelly , Bryan Ayanna S. , Garcia Veronica J. , Bucher Dirk
Published: November 2012

We studied how similar postsynaptic responses are maintained in the face of interindividual variability in the number of presynaptic neurons. In the stomatogastric ganglion of the lobster,Homarus americanus, the pyloric (PY) neurons exist in variable numbers across animals. We show that each individual fiber of the stomach muscles innervated by PY neurons received synaptic input from all neurons present. We performed intracellular recordings of excitatory junction potentials (EJPs) in the muscle fibers to determine the consequences of differences in the number of motor neurons. Despite the variability in neuron number, the compound electrical response of muscle fibers to natural bursting input was similar across individuals. The similarity of total synaptic activation was not due to differences in the spiking activity of individual motor neurons across animals with different numbers of PY neurons. The amplitude of a unitary EJP in response to a single spike in a single motor neuron also did not depend on the number of PY neurons present. Consequently, the compound EJP in response to a single stimulus that activated all motor axons present was larger in individuals with more PY neurons. However, when axons were stimulated with trains of pulses mimicking bursting activity, EJPs facilitated more in individuals with fewer PY neurons. After a few stimuli, this resulted in depolarizations similar to the ones in individuals with more PY neurons. We interpret our findings as evidence that compensatory or homeostatic regulatory mechanisms can act on short-term synaptic dynamics instead of absolute synaptic strength.
Somatosensory Projections to Cochlear Nucleus Are Upregulated after Unilateral Deafness
Authors: Zeng Chunhua , Yang Ziheng , Shreve Lauren , Bledsoe Sanford , Shore Susan
Published: November 2012

The cochlear nucleus (CN) receives innervation from auditory and somatosensory structures, which can be identified using vesicular glutamate transporters, VGLUT1 and VGLUT2. VGLUT1 is highly expressed in the magnocellular ventral CN (VCN), which receives auditory nerve inputs. VGLUT2 is predominantly expressed in the granule cell domain (GCD), which receives nonauditory inputs from somatosensory nuclei, including spinal trigeminal nucleus (Sp5) and cuneate nucleus (Cu). Two weeks after unilateral deafening VGLUT1 is significantly decreased in ipsilateral VCN while VGLUT2 is significantly increased in the ipsilateral GCD (Zeng et al., 2009), putatively reflecting decreased inputs from auditory nerve and increased inputs from nonauditory structures in guinea pigs. Here, we wished to determine whether the upregulation of VGLUT2 represents increases in the number of somatosensory projections to the CN that are maintained for longer periods of time. Thus, we examined concurrent changes in VGLUT levels and somatosensory projections in the CN using immunohistochemistry combined with anterograde tract tracing three and six weeks following unilateral deafening. The data reveal that unilateral deafness leads to increased numbers of VGLUT2-colabeled Sp5 and Cu projections to the ventral and dorsal CN. These findings suggest that Sp5 and Cu play significant and unique roles in cross-modal compensation and that, unlike after shorter term deafness, neurons in the magnocellular regions also participate in the compensation. The enhanced glutamatergic somatosensory projections to the CN may play a role in neural spontaneous hyperactivity associated with tinnitus.
Searching for the Mismatch Negativity in Primary Auditory Cortex of the Awake Monkey: Deviance Detection or Stimulus Specific Adaptation?
Authors: Fishman Yonatan I. , Steinschneider Mitchell
Published: November 2012

The mismatch negativity (MMN) is a preattentive component of the auditory event-related potential that is elicited by a change in a repetitive acoustic pattern. While MMN has been extensively used in human electrophysiological studies of auditory processing, the neural mechanisms and brain regions underlying its generation remain unclear. We investigate possible homologs of the MMN in macaque primary auditory cortex (A1) using a frequency oddball paradigm in which rare “deviant” tones are randomly interspersed among frequent “standard” tones. Standards and deviants had frequencies equal to the best frequency (BF) of the recorded neural population or to a frequency that evoked a response half the amplitude of the BF response. Early and later field potentials, current source density components, multiunit activity, and induced high-gamma band responses were larger when elicited by deviants than by standards of the same frequency. Laminar analysis indicated that differences between deviant and standard responses were more prominent in later activity, thus suggesting cortical amplification of initial responses driven by thalamocortical inputs. However, unlike the human MMN, larger deviant responses were characterized by the enhancement of “obligatory” responses rather than the introduction of new components. Furthermore, a control condition wherein deviants were interspersed among many tones of variable frequency replicated the larger responses to deviants under the oddball condition. Results suggest that differential responses under the oddball condition in macaque A1 reflect stimulus-specific adaptation rather than deviance detection per se. We conclude that neural mechanisms of deviance detection likely reside in cortical areas outside of A1.
Thalamocortical Asynchrony in Conditions of Spinal Cord Injury Pain in Rats
Authors: Seminowicz David A. , Jiang Li , Ji Yadong , Xu Su , Gullapalli Rao P. , Masri Radi
Published: November 2012

Spinal cord injury (SCI) pain is a debilitating chronic condition that is severe and unrelenting. Despite decades of extensive research, the neuropathological mechanisms responsible for the development of this devastating condition remain largely unknown, hindering our ability to develop effective treatments. Because several lines of evidence implicate abnormalities of the thalamus and cortex in the etiology of SCI pain, we hypothesized that SCI pain results from abnormal functional connectivity of brain areas heavily implicated in pain processing. We performed a longitudinal study in a rat model of SCI (SCI group,n= 8; sham-operated group,n= 6) and acquired resting-state functional magnetic resonance imaging scans before spinal surgery and 3, 7, 14, and 21 (SCI only) days after surgery in the same animals. Functional connectivity was decreased between the ventroposterior lateral thalamus (VPL) and primary somatosensory cortex (S1) 7 d after SCI. This reduction preceded an increase in connectivity between S1 and other cortical areas involved in nociceptive processing. In addition, VPL had increased connectivity to contralateral thalamus at 7 and 14 d after injury. The temporal pattern of the increase in functional connectivity within the thalamus and between cortical areas (particularly S1 and retrosplenial cortex) had a striking resemblance to the temporal pattern for the development of a “below-level” mechanical hypersensitivity in the same animals. Our findings suggest that below-level hypersensitivity is associated with functional disconnection (asynchrony) between the thalamus and cortical areas involved in nociceptive processing.
The Neural Correlates of Recollection: Transient Versus Sustained fMRI Effects
Authors: Vilberg Kaia L. , Rugg Michael D.
Published: November 2012

Prior research has identified several regions where neural activity is enhanced when recollection of episodic information is successful. Here, we investigated whether these regions dissociate according to whether recollection-related activity is transient or sustained across the time that recollected information must be maintained before a behavioral judgment. Human subjects studied a series of word-picture pairs under the requirement to judge which of the denoted objects was smaller. Following each of 4 study sessions, a scanned test phase occurred in which a series of studied and unstudied words was presented. The requirement at test was to judge whether each word was old or new and, if judged old, to retrieve the associated study picture and hold it in mind until a cue appeared. The delay interval varied between two and eight seconds. The cue instructed subjects which of three different judgments should be applied to the retrieved picture. Separate responses were required when words were either deemed new or the associated image was not retrieved. Relative to studied words for which the associated picture could not be retrieved, words giving rise to successful recollection elicited transient responses in the hippocampus/parahippocampal cortex and retrosplenial cortex, and to sustained activity in prefrontal cortex, the intraparietal sulcus, the left angular gyrus and the inferior temporal gyrus. The finding that recollection-related activity in the angular gyrus tracked the period over which recollected information was maintained is consistent with the proposal that this region contributes to the online representation of recollected information.
BMP4 Sufficiency to Induce Choroid Plexus Epithelial Fate from Embryonic Stem Cell-Derived Neuroepithelial Progenitors
Authors: Watanabe Momoko , Kang Young-Jin , Davies Lauren M. , Meghpara Sanket , Lau Kimbley , Chung Chi-Yeh , Kathiriya Jaymin , Hadjantonakis Anna-Katerina , Monuki Edwin S.
Published: November 2012

Choroid plexus epithelial cells (CPECs) have essential developmental and homeostatic roles related to the CSF and blood–CSF barrier they produce. Accordingly, CPEC dysfunction has been implicated in many neurological disorders, such as Alzheimer's disease, and transplant studies have provided proof-of-concept for CPEC-based therapies. However, such therapies have been hindered by the inability to expand or generate CPECs in culture. During development, CPECs differentiate from preneurogenic neuroepithelial cells and require bone morphogenetic protein (BMP) signaling, but whether BMPs suffice for CPEC induction is unknown. Here we provide evidence for BMP4 sufficiency to induce CPEC fate from neural progenitors derived from mouse embryonic stem cells (ESCs). CPEC specification by BMP4 was restricted to an early time period after neural induction in culture, with peak CPEC competency correlating to neuroepithelial cells rather than radial glia. In addition to molecular, cellular, and ultrastructural criteria, derived CPECs (dCPECs) had functions that were indistinguishable from primary CPECs, including self-assembly into secretory vesicles and integration into endogenous choroid plexus epithelium following intraventricular injection. We then used BMP4 to generate dCPECs from human ESC-derived neuroepithelial cells. These findings demonstrate BMP4 sufficiency to instruct CPEC fate, expand the repertoire of stem cell-derived neural derivatives in culture, and herald dCPEC-based therapeutic applications aimed at the unique interface between blood, CSF, and brain governed by CPECs.
DUSP6/MKP3 is overexpressed in papillary and poorly differentiated thyroid carcinoma and contributes to neoplastic properties of thyroid cancer cells
Authors: Degl'Innocenti Debora , Romeo Paola , Tarantino Eva , Sensi Marialuisa , Cassinelli Giuliana , Catalano Veronica , Lanzi Cinzia , Perrone Federica , Pilotti Silvana , Seregni Ettore , Pierotti Marco A , Greco Angela , Borrello Maria Grazia
Published: November 2012

Thyroid carcinomas derived from follicular cells comprise papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, poorly differentiated thyroid carcinoma (PDTC) and undifferentiated anaplastic thyroid carcinoma (ATC). PTC, the most frequent thyroid carcinoma histotype, is associated with gene rearrangements that generateRET/PTCandTRKoncogenes and withBRAF-V600Eand RAS gene mutations. These last two genetic lesions are also present in a fraction of PDTCs. The ERK1/2 pathway, downstream of the known oncogenes activated in PTC, has a central role in thyroid carcinogenesis. In this study, we demonstrate that theBRAF-V600E,RET/PTC, andTRKoncogenes upregulate the ERK1/2 pathway's attenuator cytoplasmic dual-phase phosphatase DUSP6/MKP3 in thyroid cells. We also show DUSP6 overexpression at the mRNA and protein levels in all the analysed PTC cell lines. Furthermore,DUSP6mRNA was significantly higher in PTC and PDTC in comparison with normal thyroid tissues both in expression profile datasets and in patients' surgical samples analysed by real-time RT-PCR. Immunohistochemical and western blot analyses showed that DUSP6 was also overexpressed at the protein level in most PTC and PDTC surgical samples tested, but not in ATC, and revealed a positive correlation trend with ERK1/2 pathway activation. Finally,DUSP6silencing reduced the neoplastic properties of four PTC cell lines, thus suggesting thatDUSP6may have a pro-tumorigenic role in thyroid carcinogenesis.
Daldinia eschscholtzii (Ascomycota, Xylariaceae) isolated from the Brazilian Amazon: taxonomic features and mycelial growth conditions
Authors: Yuyama Kamila Tomoko , Pereira Jadergudson , Maki Cristina Sayuri , Ishikawa Noemia Kazue
Published: November 2012

The Amazon has a high diversity of fungi, including species of the genus Daldinia (Ascomycota, Xylariaceae), which produce secondary metabolites with recognized nematicidal and antimicrobial activity. The ecological role of Daldinia is important, as stromata serve as refuges to many insects and arthropodes, and the fungi contribute to the degradation of vegetable organic matter. The aim of this study was to analyze the taxonomic features and mycelial growth conditions in vitro of a Daldinia specimen collected in the Brazilian Amazon. Morphological and molecular studies of the fungus identified it as D. eschscholtzii. To evaluate mycelial growth, we cultivated the fungus at 20, 25, 30, 35, and 40 °C in malt extract-peptone agar (MEPA), malt extract-peptone (MEP), potato dextrose (PD), and minimum medium (MM). The best mycelial growth occurred at 35 °C, although the greatest amount of biomass was obtained at 25 °C and 30 °C. PD proved to be the best medium for biomass production.
Avaliação do programa de controle da tuberculose em cenário Amazônico: desafios em Coari
Authors: Heufemann Nicolás Esteban Castro , Gonçalves Maria Jacirema Ferreira , Garnelo Maria Luiza
Published: November 2012

Pesquisa avaliativa, tipo estudo de caso, do contexto e grau de implantação do Programa de Controle da Tuberculose (PCT) no município de Coari, Amazonas, 2001-2008. As técnicas de pesquisa conjugaram abordagens quantitativa e qualitativa, com uso de modelo lógico e matriz de julgamento. O componente quantitativo utilizou dados do Sistema de Informação de Agravos de Notificação e dados populacionais do Departamento de Informática do Sistema Único de Saúde. As variáveis foram, idade, sexo, forma clínica, procedência, tipo de entrada, meios diagnósticos e situação de encerramento. Para a população foram feitos cálculos de interpolação geométrica, por faixa etária, sexo e procedência (urbana e rural). O componente qualitativo combinou técnicas e fontes: pesquisa documental; observação e entrevista. O modelo lógico propiciou o entendimento da estrutura, processo e resultado do PCT; e a matriz de julgamento permitiu identificar o grau de implantação. A taxa média de incidência da tuberculose na área urbana foi 27 casos por 100.000 habitantes e de 9,4 por 100.000 habitantes na área rural, com razão masculino/feminino de 1,6. A avaliação do contexto externo, vigilância epidemiológica e operacionalização do PCT mostrou grau de implantação intermediário. No contexto organizacional, estrutura física das Unidades Saúde, recursos humanos e efetividade, o resultado foi incipiente. No geral, o grau de implantação foi intermediário. A flutuação nas notificações e taxas anuais de incidência, associada ao não cumprimento das metas do PCT, à desarticulação entre o PCT e o restante da atenção básica e à não interiorização da assistência indicam sérias dificuldades na operacionalização das ações de controle da tuberculose.