bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of antigen specific recognition and cell mediated cytotoxicity by a modified lysispot assay in a rat colon carcinoma model
Authors: Bordignon Valentina , Cordiali-Fei Paola , Rinaldi Monica , Signori Emanuela , Cottarelli Andrea , Zonfrillo Manuela , Ensoli Fabrizio , Rasi Guido , Fuggetta Maria Pia
Published: February 2012

Background

Antigen-specific CD8+ cytotoxic T lymphocytes represent potent effector cells of the adaptive immune response against viruses as well as tumours. Therefore assays capable at exploring the generation and function of cytotoxic T lymphocytes represent an important objective for both clinical and experimental settings.

Methods

Here we show a simple and reproducible assay for the evaluation of antigen-specific CD8+ cytotoxic T lymphocytes based on a LysiSpot technique for the simultaneous determination of antigen-specific IFN-γ production and assessment of tumor cytolysis. The assay was developed within an experimental model of colorectal carcinoma, induced by the colorectal tumor cell line DHD-K12 that induces tumors in BDIX rats and, in turn, elicits a tumor- specific immune response.

Results

Using DHD-K12 cells transfected to express Escherichia coli β-galactosidase as target cells, and by the fine setting of spot colours detection, we have developed an in vitro assay that allows the recognition of cytotoxic T lymphocytes induced in BDIX rats as well as the assessment of anti-tumour cytotoxicity. The method highlighted that in the present experimental model the tumour antigen-specific immune response was bound to killing target cells in the proportion of 55%, while 45% of activated cells were not cytotoxic but released IFN-γ. Moreover in this model by an ELISPOT assay we demonstrated the specific recognition of a nonapeptide epitope called CSH-275 constitutionally express in DHD-K12 cells.

Conclusions

The assay proved to be highly sensitive and specific, detecting even low frequencies of cytotoxic/activated cells and providing the evaluation of cytokine-expressing T cells as well as the extent of cytotoxicity against the target cells as independent functions. This assay may represent an important tool to be adopted in experimental settings including the development of vaccines or immune therapeutic strategies
Foundation for what? Commentary on … Current position of psychiatry in UK foundation schools
Authors: Bhugra Dinesh
Published: February 2012

Two years of foundation training were added to the medical students' transition from learning theory in medical school to trainee clinical practice, replacing one year of house jobs or internship. In the recent few years there has been a tremendous amount of debate about undergraduate medical training and changes in regulations which led to the Collins review in 2010. The review proposed that trainees need more exposure to community-based placements such as psychiatry, public health and community paediatrics and that they also need to learn to deal with chronic conditions. Bearing in mind that nearly a third of the general practitioner's patients will have psychiatric problems, it is essential that all doctors gain some exposure to psychiatric practice. It is crucial that this exposure is appropriate and adequate so that the next generation of doctors can provide accessible services that patients will be willing to use.
Dynamic Regulation of Wnt7a Expression in the Primate Endometrium: Implications for Postmenstrual Regeneration and Secretory Transformation
Authors: Fan Xiujun , Krieg Sacha , Hwang Jong Yun , Dhal Sabita , Kuo Calvin J. , Lasley Bill L. , Brenner Robert M. , Nayak Nihar R.
Published: February 2012

Despite the vital physiological role of endometrial regeneration during the menstrual cycle and the various pathological implications of abnormal growth of endometrial epithelial cells, the local factors and regulatory mechanisms involved in endometrial regeneration and growth have not been well characterized. Here, we examine the pattern, hormone dependence, and potential functions of Wnt7a (wingless-type MMTV integration site family member 7a), which is known to play a critical role in the formation of the mouse endometrial epithelium during embryonic development, in both human and artificially cycling rhesus macaque endometrium, and using a potent Wnt-antagonist in a mouse model of endometrial regeneration. Wnt7a transcript levels were examined using quantitative real-time PCR and in situ hybridization, and immunohistochemistry was performed to detect Ki-67 and 3,5-bromodeoxyuridine. Stringent, fully conditional Wnt inhibition was achieved by adenoviral expression of Dickkopf-1 during artificial endometrial regeneration in mice. In macaques, Wnt7a expression was confined to the newly formed luminal epithelium (LE) and upper glands during the postmenstrual repair phase. The signal increased in the LE during the proliferative phase but decreased in the upper glands and was undetectable in the glands by the late proliferative phase. Interestingly, Wnt7a was completely suppressed in the LE and remained undetectable in other cell types after 7 d of progesterone treatment. The pattern of Wnt7a expression in the human endometrium was similar to that in macaques. Blockade of Wnt signaling during endometrial regeneration in mice resulted in a dramatic delay in reepithelialization and degeneration of glands and LE. These results strongly suggest, for the first time, a role for Wnt7a in postmenstrual regeneration and proliferation of endometrial glands and LE in primates, and its dramatic suppression by progesterone is likely essential for secretory transformation of the epithelium.
Long-Term Fgf23 Deficiency Does Not Influence Aging, Glucose Homeostasis, or Fat Metabolism in Mice with a Nonfunctioning Vitamin D Receptor
Authors: Streicher Carmen , Zeitz Ute , Andrukhova Olena , Rupprecht Anne , Pohl Elena , Larsson Tobias E. , Windisch Wilhelm , Lanske Beate , Erben Reinhold G.
Published: February 2012

It is still controversial whether the bone-derived hormone fibroblast growth factor-23 (FGF23) has additional physiological functions apart from its well-known suppressive actions on renal phosphate reabsorption and vitamin D hormone synthesis. Here we analyzed premature aging, mineral homeostasis, carbohydrate metabolism, and fat metabolism in 9-month-old male wild-type (WT) mice, vitamin D receptor mutant mice (VDRΔ/Δ) with a nonfunctioning vitamin D receptor, and Fgf23−/−/VDRΔ/Δ compound mutant mice on both a standard rodent chow and a rescue diet enriched with calcium, phosphorus, and lactose. Organ atrophy, lung emphysema, and ectopic tissue or vascular calcifications were absent in compound mutants. In addition, body weight, glucose tolerance, insulin tolerance, insulin secretory capacity, pancreatic beta cell volume, and retroperitoneal and epididymal fat mass as well as serum cholesterol and triglycerides were indistinguishable between vitamin D receptor and compound mutants. In contrast to VDRΔ/Δ and Fgf23−/−/VDRΔ/Δ mice, which stayed lean, WT mice showed obesity-induced insulin resistance. To rule out alopecia and concomitantly elevated energy expenditure present in 9-month-old VDRΔ/Δ and Fgf23−/−/VDRΔ/Δ mice as a confounding factor for the lacking effect of Fgf23 deficiency on fat mass, we analyzed whole-body composition in WT, Fgf23−/−, VDRΔ/Δ, and Fgf23−/−/VDRΔ/Δ mice at the age of 4 wk, when the coat in VDRΔ/Δ mice is still normal. Whole-body fat mass was reduced in Fgf23−/− mice but almost identical in WT, VDRΔ/Δ, and Fgf23−/−/VDRΔ/Δ mice. In conclusion, our data indicate that Fgf23 has no molecular vitamin D-independent role in aging, insulin signaling, or fat metabolism in mice.
Community Structure and Market Outcomes: A Repeated Games-in-Networks Approach
Authors: Fainmesser Itay P
Published: February 2012

Consider a large market with asymmetric information, in which sellers have the option to “cheat” their buyers, and buyers decide whether to repurchase from different sellers. We model active trade relationships as links in a buyer-seller network and study repeated games in such networks. Endowing sellers with incomplete knowledge of the network, we derive conditions that determine whether a network is consistent with cooperation between every buyer and seller that are connected. Three network features reduce the minimal discount factor sufficient for cooperation: moderate and balanced competition, sparseness, and segregation. Incentive constraints are binding and rule out efficient networks. (JEL C73, D82, D85, Z13)
Partially Specified Probabilities: Decisions and Games
Authors: Lehrer Ehud
Published: February 2012

The paper develops a theory of decision making based on partially specified probabilities. It takes an axiomatic approach using Anscombe and Aumann's (1963) setting, and is based on the concave integral for capacities. This theory is then expanded to interactive models in order to extend Nash equilibrium by introducing the concept of partially specified equilibrium. (JEL C70, D81, D83)
Will There Be Blood? Incentives and Displacement Effects in Pro-Social Behavior
Authors: Lacetera Nicola , Macis Mario , Slonim Robert
Published: February 2012

We present evidence from nearly 14,000 American Red Cross blood drives and from a natural field experiment showing that economic incentives have a positive effect on blood donations without increasing the fraction of donors who are ineligible to donate. The effect increases with the incentive's economic value. However, a substantial proportion of the increase in donations is explained by donors leaving neighboring drives without incentives to attend drives with incentives; this displacement also increases with the economic value of the incentive. We conclude that extrinsic incentives stimulate pro-social behavior, but unless displacement effects are considered, the effect may be overestimated. (JEL D64, H41, I12)
Regulation, Ownership, and Costs: A Historical Perspective from Indian Railways
Authors: Bogart Dan , Chaudhary Latika
Published: February 2012

This paper studies the relationship between operational costs and state ownership in Indian railways between 1874 and 1912. We find the move to state ownership significantly decreased working expenses. The cost declines are not driven by anticipation effects, changes in reporting standards, or long run trends. Rather, the evidence suggests the colonial Government of India reduced operational costs by cutting labor costs. Our surprising results can be explained by the undemocratic colonial nature of the Government of India, a fiscal system heavily reliant on railways for revenues, and a regulatory environment under private ownership that weakened incentives to lower costs. (JEL L32, L51, L92, N45, N75, O18, R41)
Reject analysis in direct digital radiography
Authors: Andersen Eivind Richter , Jorde Jannike , Taoussi Nadia , Yaqoob Sadia Halima , Konst Bente , Seierstad Therese
Published: January 2012

Background

Reject analysis can be used as a quality indicator, and is an important tool in localizing areas where optimization is required. Reducing number of rejects is important yielding reduced patient exposure and increased cost-effectiveness.

Purpose

To determine rejection rates and causes in direct digital radiography.

Material and Methods

Data were collected during a three-month period in spring 2010 at two direct digital laboratories in Norway. All X-ray examinations, types, numbers, and reasons for rejections were obtained using automatic reject analysis software. Thirteen causes for rejection could be selected.

Results

Out of the 27,284 acquired images, 3206 were rejected, yielding an overall rejection rate of 12%. Highest rejection rates were found for examination of knees, shoulders, and wrist. In all, 77% of the rejected images arose from positioning errors.

Conclusion

An overall rejection rate of 12% indicates a need for optimizing radiographic practice in the department.
Carcinoma ex pleomorphic adenoma of the parotid gland
Authors: Kashiwagi Nobuo , Murakami Takamichi , Chikugo Takaaki , Tomita Yasuhiko , Kawano Kiyoshi , Nakanishi Katsuyuki , Mori Kazunori , Tomiyama Noriyuki
Published: January 2012

Background

Carcinoma ex pleomorphic adenoma (CXPA) is a rare aggressive epithelial malignancy arising from a primary or recurrent benign mixed tumor. Only a few case reports describing the radiologic features of CXPA have been published.

Purpose

To describe and characterize the magnetic resonance (MR) imaging findings of CXPA in the parotid gland and correlate them with pathologic findings.

Material and Methods

The MR images of surgically proven CXPA in the parotid gland of five men and five women ranging in age from 28 to 75 years (mean 52 years) were retrospectively reviewed. All MR images were evaluated with emphasis on the size, margin characteristics, extraparotid infiltration, the presence of an encapsulated component, and signal intensity on T2-weighted or short-inversion-time inversion recovery (STIR) images.

Results

The average maximal diameter was 4.3 cm. All 10 tumors had ill-defined boundaries, and seven tumors showed extraparotid infiltration, reflecting invasive growth of the malignant component identified on histological examination. Eight tumors had a round encapsulated component and seven of those signal intensities were a mixture of hypo- and hyperintensity on T2-weighted or STIR images. Histological correlation of these components revealed fibrously encapsulated tumors containing hyalinization and myxoid tissue, suggesting degenerated pleomorphic adenoma. Invasive malignant components had non-specific and various signal intensities.

Conclusion

An invasive parotid mass co-existing with a round encapsulated component is suggestive of carcinoma ex pleomorphic adenoma.
Detection and size of pulmonary lesions: how accurate is MRI? A prospective comparison of CT and MRI
Authors: Heye Tobias , Ley Sebastian , Heussel Claus Peter , Dienemann Hendrik , Kauczor Hans-Ulrich , Hosch Waldemar , Libicher Martin
Published: January 2012

Background

Although CT is the modality of choice for morphological lung imaging, an increasing proportion of chest imaging is performed by MRI due to the utilization of whole-body MRI. Therefore, the diagnostic performance of MRI in reliably detecting pulmonary lesions should be established.

Purpose

To investigate the detection rate of pulmonary lesions by MRI that can be expected in a clinical setting and to assess the accuracy of lesion measurement by MRI compared to CT.

Material and Methods

Twenty-eight patients (median age 66 years) with indication for CT imaging due to suspected thoracic malignancy were prospectively included. Chest MRI performed on the same day as CT, comprised unenhanced TrueFisp, ecg-gated T2-weighted HASTE, T1-weighted VIBE, and contrast-enhanced T1-weighted, fat-saturated VIBE sequences. MR sequences were evaluated for lesion detection by two readers independently and measurement of lesion size was performed. MR findings were correlated with CT.

Results

One hundred and eight pulmonary lesions (20 thoracic malignancies, 88 lung nodules) were detected by CT in 26 patients. Lesions were ruled out in two patients. All thoracic malignancies were identified by MRI with strong correlation ( r = 0.97−0.99; P < 0.01) in lesion size measurement compared to CT. Unenhanced, T1-weighted VIBE correctly classified 94% of thoracic malignancies into T-stages. Contrast-enhanced, T1-weighted VIBE performed best in identifying 36% of lung nodules, 40% were detected combining unenhanced and contrast-enhanced T1-weighted VIBE. Detection rate increased to 65% for the combined sequences regarding lesions ≥5 mm. Lesion size measurement by all MR sequences strongly correlated with CT ( r = 0.96−0.97; P = 0.01).

Conclusion

MRI is as accurate as CT in detection and size measurement of primary thoracic malignancies >1 cm in diameter. If a lung lesion is detected by MRI, it is a reliable finding and its measurement is accurate. CT remains superior in detecting small lung nodules (<6 mm). Detection rate of MRI for small lesions is improved using a multi-sequence protocol including contrast administration.
Value of percutaneous embolotherapy for the management of traumatic vascular limb injury
Authors: Maleux Geert , Herten Pieter-Jan , Vaninbroukx Johan , Thijs Marleen , Nijs Stefaan , Fourneau Inge , Heye Sam
Published: January 2012

Background

Arterial injuries to the extremities may result in severe hemorrhagic complications. Open surgical repair has been the standard of care for these patients, but endovascular management may be a valuable, less invasive alternative.

Purpose

To evaluate the safety, efficacy and long-term durability of embolotherapy for the management of hemorrhagic, traumatic vascular injuries in upper and lower limbs.

Material and Methods

Patients with traumatic or iatrogenic hemorrhagic vascular injuries to the extremities and managed with endovascular embolotherapy in the authors' institution between 1998 and 2010 were included in this retrospective study. Embolization was performed with different embolic materials; technical and long-term clinical outcome was assessed by review of the medical records or by telephone interviews of the referring physicians.

Results

Embolization was performed in 31 patients. In six patients the vascular lesion was traumatic, in the remaining 25 patients the lesion was of iatrogenic origin. Angiographic vascular lesions identified were: contrast extravasation ( n = 19, 61%), pseudoaneurysm ( n = 8, 26%), and pseudoaneurysm with arteriovenous fistula ( n = 3, 10%). Primary and secondary clinical success was obtained in 84% and 97% of cases, respectively. Procedure-related complications occurred in five patients (16%). Most of them were mild. One patient expired 34 days after the procedure due to amputation-stump infection, septicaemia, and multiple organ failure. Long-term outcome showed no recurrent bleeding or other embolization-related complications.

Conclusion

Embolotherapy for the management of hemorrhagic, traumatic vascular injuries in upper and lower limbs is relatively safe, very effective without recurrence or other embolization-related symptoms.
Prevalence and patterns of renal involvement in imaging of malignant lymphoproliferative diseases
Authors: Bach Andreas Gunter , Behrmann Curd , Holzhausen Hans Jürgen , Katzer Michaela , Arnold Dirk , Spielmann Rolf Peter , Surov Alexey
Published: January 2012

Background

Renal involvement in patients with lymphoproliferative disease is an uncommon radiological finding.

Purpose

To determine its prevalence and radiological appearances in a patient population.

Material and Methods

All forms of lymphoproliferative disease (ICD: C81–C96) were considered. From January 2005 to January 2010, 668 consecutive patients with lymphoproliferative disease were identified with the help of the radiological database and patient records. Inclusion criteria were complete staging including appropriate CT scan and/or MRI. All stored images (initial staging and follow-up examinations) were reviewed.

Results

Review of all stored images revealed renal infiltration in patients with non-Hodgkin lymphoma (11 of 364 = 3.0%; median age = 65 years, m:f = 6:5) but also multiple myeloma (2 of 162 = 1.2%; median age = 72 years; m:f = 1:1) and leukemia (5 of 101 = 4.9%; median age = 12 years; m:f = 2:3). There were no cases of renal infiltration in 41 patients with Hodgkin's disease. In total there were six patients with solitary lesions, five patients with diffuse renal enlargement, four patients with perirenal lesions, and two patients with direct invasion of the kidney.

Conclusion

In leukemia the most common imaging pattern is diffuse enlargement. In the other subtypes of lymphoproliferative disease no specific correlation between typical CT patterns and subtype of lymphoproliferative disease can be found. The prevalence of renal involvement is in line with earlier studies. Contrary to earlier reports, multiple lesions were not found to be a common pattern.
Patients with Non-diagnostic Hyperamylasaemia Must be Investigated and Managed as per Acute Pancreatitis
Authors: Jones Huw G , Jardine Nicky , Williamson Jeremy , Puntis Malcolm CA , Morris-Stiff Gareth J
Published: January 2012

Objectives

The identification of hyperamylasaemia insufficient to confidently diagnose acute pancreatitis in patients with epigastric pain poses a clinical dilemma. The aim of this study was to identify a cohort of such patients and review their presentation, investigation and outcome.

Design

Patients admitted through the emergency surgical intake during a 12-month period with serum amylase levels of 100–400 IU/L were identified and case notes reviewed to confirm those presenting with upper abdominal pain. Subsequent radiological and biochemical investigations were recorded.

Participants

A total of 25 patients with non-diagnostic hyperamylasaemia.

Setting

Ward patients in a University Hospital.

Main outcome measures

Amylase level, eventual diagnosis, drug history.

Results

Twenty-five patients were identified with a mean age of 46.7 years. The median serum amylase level was 230 IU/L (range 102–358 IU/L). Twenty-two patients underwent transabdominal ultrasound at presentation, with gallstones identified in nine cases. The remaining three had documented gallstones and were awaiting elective cholecystectomy. Of the 13 patients with no evidence of cholelithiasis, six were taking medications known to cause pancreatitis, seven patients underwent computed tomography (CT) scans that identified chronic pancreatitis in three, and were non-diagnostic in four cases. These four patients underwent endoscopic ultrasound (EUS) evaluation of the biliary tree identifying microlithiasis in one but no pathology in the remaining three cases.

Conclusions

Patients with hyperamylasaemia not diagnostic of pancreatitis should be carefully investigated, as gallstones will be identified in at least 50%. An accurate drug history is also invaluable.
Kinetics of tRNA folding monitored by aminoacylation
Authors: Bhaskaran Hari , Rodriguez-Hernandez Annia , Perona John J.
Published: January 2012

We describe a strategy for tracking Mg2+-initiated folding of 32P-labeled tRNA molecules to their native structures based on the capacity for aminoacylation by the cognate aminoacyl-tRNA synthetase enzyme. The approach directly links folding to function, paralleling a common strategy used to study the folding of catalytic RNAs. Incubation of unfolded tRNA with magnesium ions, followed by the addition of aminoacyl-tRNA synthetase and further incubation, yields a rapid burst of aminoacyl-tRNA formation corresponding to the prefolded tRNA fraction. A subsequent slower increase in product formation monitors continued folding in the presence of the enzyme. Further analysis reveals the presence of a parallel fraction of tRNA that folds more rapidly than the majority of the population. The application of the approach to study the influence of post-transcriptional modifications in folding of Escherichia coli tRNA1Gln reveals that the modified bases increase the folding rate but do not affect either the equilibrium between properly folded and misfolded states or the folding pathway. This assay allows the use of 32P-labeled tRNA in integrated studies combining folding, post-transcriptional processing, and aminoacylation reactions.
The 5′ UTR of HIV-1 full-length mRNA and the Tat viral protein modulate the programmed −1 ribosomal frameshift that generates HIV-1 enzymes
Authors: Charbonneau Johanie , Gendron Karine , Ferbeyre Gerardo , Brakier-Gingras Léa
Published: January 2012

Translation of the full-length messenger RNA (mRNA) of the human immunodeficiency virus type 1 (HIV-1) generates the precursor of the viral enzymes via a programmed −1 ribosomal frameshift. Here, using dual-luciferase reporters, we investigated whether the highly structured 5′ untranslated region (UTR) of this mRNA, which interferes with translation initiation, can modulate HIV-1 frameshift efficiency. We showed that, when the 5′ UTR of HIV-1 mRNA occupies the 5′ end of the reporter mRNA, HIV-1 frameshift efficiency is increased about fourfold in Jurkat T-cells, compared with a control dual-luciferase reporter with a short unstructured 5′ UTR. This increase was related to an interference with cap-dependent translation initiation by the TAR-Poly(A) region at the 5′ end of the messenger. HIV-1 mRNA 5′ UTR also contains an internal ribosome entry site (IRES), but we showed that, when the cap-dependent initiation mode is available, the IRES is not used or is weakly used. However, when the ribosomes have to use the IRES to translate the dual-luciferase reporter, the frameshift efficiency is comparable to that of the control dual-luciferase reporter. The decrease in cap-dependent initiation and the accompanying increase in frameshift efficiency caused by the 5′ UTR of HIV-1 mRNA is antagonized, in a dose-dependent way, by the Tat viral protein. Tat also stimulates the IRES-dependent initiation and decreases the corresponding frameshift efficiency. A model is presented that accounts for the variations in frameshift efficiency depending on the 5′ UTR and the presence of Tat, and it is proposed that a range of frameshift efficiencies is compatible with the virus replication.
A Small, Lightweight Borehole Receiver for Crosshole and Downhole Seismic Testing
Authors: Kalinski M. E.
Published: February 2012

Crosshole and downhole seismic testing have traditionally employed the use of a downhole receiver consisting of geophones in a sealed container along with a separate inflatable bladder for seating the geophones against the inside of the boring. This configuration has been used with success, but these receivers can be relatively large and heavy. As an alternative, a smaller, lighter borehole receiver design has been developed. The prototype tool is approximately 19 cm (7.5 in.) long and 6.4 cm (2.5 in.) in diameter, and it weighs less than 0.68 kg (1.5 lb). The new design is a single pressuremeter-like unit in which small accelerometers are glued to the inside of an inflatable membrane. When inflated, the accelerometers are pressed against the borehole wall or casing, and excellent coupling is achieved. Typical results from field testing indicate that the new tool produces reliable results.
Specialized Cortical Subnetworks Differentially Connect Frontal Cortex to Parahippocampal Areas
Authors: Hirai Yasuharu , Morishima Mieko , Karube Fuyuki , Kawaguchi Yasuo
Published: February 2012

How information is manipulated and segregated within local circuits in the frontal cortex remains mysterious, in part because of inadequate knowledge regarding the connectivity of diverse pyramidal cell subtypes. The frontal cortex participates in the formation and retrieval of declarative memories through projections to the perirhinal cortex, and in procedural learning through projections to the striatum/pontine nuclei. In rat frontal cortex, we identified two pyramidal cell subtypes selectively projecting to distinct subregions of perirhinal cortex (PRC). PRC-projecting cells in upper layer 2/3 (L2/3) of the frontal cortex projected to perirhinal area 35, while neurons in L5 innervated perirhinal area 36. L2/3 PRC-projecting cells partially overlapped with those projecting to the basolateral amygdala. L5 PRC-projecting cells partially overlapped with crossed corticostriatal cells, but were distinct from neighboring corticothalamic (CTh)/corticopontine cells. L5 PRC-projecting and CTh cells were different in their electrophysiological properties and dendritic/axonal morphologies. Within the frontal cortex, L2/3 PRC-projecting cells innervated L5 PRC-projecting and CTh cells with similar probabilities, but received feedback excitation only from PRC-projecting cells. These data suggest that specific neuron subtypes in different cortical layers are reciprocally excited via interlaminar loops. Thus, two interacting output channels send information from the frontal cortex to different hierarchical stages of the parahippocampal network, areas 35 and 36, with additional collaterals selectively targeting the amygdala or basal ganglia, respectively. Combined with the hierarchical connectivity of PRC-projecting and CTh cells, these observations demonstrate an exquisite diversification of frontal projection neurons selectively connected according to their participation in distinct memory subsystems.
Internalized Timing of Isochronous Sounds Is Represented in Neuromagnetic Beta Oscillations
Authors: Fujioka Takako , Trainor Laurel J. , Large Edward W. , Ross Bernhard
Published: February 2012

Moving in synchrony with an auditory rhythm requires predictive action based on neurodynamic representation of temporal information. Although it is known that a regular auditory rhythm can facilitate rhythmic movement, the neural mechanisms underlying this phenomenon remain poorly understood. In this experiment using human magnetoencephalography, 12 young healthy adults listened passively to an isochronous auditory rhythm without producing rhythmic movement. We hypothesized that the dynamics of neuromagnetic beta-band oscillations (∼20 Hz)—which are known to reflect changes in an active status of sensorimotor functions—would show modulations in both power and phase-coherence related to the rate of the auditory rhythm across both auditory and motor systems. Despite the absence of an intention to move, modulation of beta amplitude as well as changes in cortico-cortical coherence followed the tempo of sound stimulation in auditory cortices and motor-related areas including the sensorimotor cortex, inferior-frontal gyrus, supplementary motor area, and the cerebellum. The time course of beta decrease after stimulus onset was consistent regardless of the rate or regularity of the stimulus, but the time course of the following beta rebound depended on the stimulus rate only in the regular stimulus conditions such that the beta amplitude reached its maximum just before the occurrence of the next sound. Our results suggest that the time course of beta modulation provides a mechanism for maintaining predictive timing, that beta oscillations reflect functional coordination between auditory and motor systems, and that coherence in beta oscillations dynamically configure the sensorimotor networks for auditory-motor coupling.
PTEN Regulation of Local and Long-Range Connections in Mouse Auditory Cortex
Authors: Xiong Qiaojie , Oviedo Hysell V. , Trotman Lloyd C. , Zador Anthony M.
Published: February 2012

Autism spectrum disorders (ASDs) are highly heritable developmental disorders caused by a heterogeneous collection of genetic lesions. Here we use a mouse model to study the effect on cortical connectivity of disrupting the ASD candidate gene PTEN (phosphatase and tensin homolog deleted on chromosome 10). Through Cre-mediated recombination, we conditionally knocked out PTEN expression in a subset of auditory cortical neurons. Analysis of long-range connectivity using channelrhodopsin-2 revealed that the strength of synaptic inputs from both the contralateral auditory cortex and from the thalamus onto PTEN-cko neurons was enhanced compared with nearby neurons with normal PTEN expression. Laser-scanning photostimulation showed that local inputs onto PTEN-cko neurons in the auditory cortex were similarly enhanced. The hyperconnectivity caused by PTEN-cko could be blocked by rapamycin, a specific inhibitor of the PTEN downstream molecule mammalian target of rapamycin complex 1. Together, our results suggest that local and long-range hyperconnectivity may constitute a physiological basis for the effects of mutations in PTEN and possibly other ASD candidate genes.
Psychophysiological Analyses Demonstrate the Importance of Neural Envelope Coding for Speech Perception in Noise
Authors: Swaminathan Jayaganesh , Heinz Michael G.
Published: February 2012

Understanding speech in noisy environments is often taken for granted; however, this task is particularly challenging for people with cochlear hearing loss, even with hearing aids or cochlear implants. A significant limitation to improving auditory prostheses is our lack of understanding of the neural basis for robust speech perception in noise. Perceptual studies suggest the slowly varying component of the acoustic waveform (envelope, ENV) is sufficient for understanding speech in quiet, but the rapidly varying temporal fine structure (TFS) is important in noise. These perceptual findings have important implications for cochlear implants, which currently only provide ENV; however, neural correlates have been difficult to evaluate due to cochlear transformations between acoustic TFS and recovered neural ENV. Here, we demonstrate the relative contributions of neural ENV and TFS by quantitatively linking neural coding, predicted from a computational auditory nerve model, with perception of vocoded speech in noise measured from normal hearing human listeners. Regression models with ENV and TFS coding as independent variables predicted speech identification and phonetic feature reception at both positive and negative signal-to-noise ratios. We found that: (1) neural ENV coding was a primary contributor to speech perception, even in noise; and (2) neural TFS contributed in noise mainly in the presence of neural ENV, but rarely as the primary cue itself. These results suggest that neural TFS has less perceptual salience than previously thought due to cochlear signal processing transformations between TFS and ENV. Because these transformations differ between normal and impaired ears, these findings have important translational implications for auditory prostheses.
Noise Overexposure Alters Long-Term Somatosensory-Auditory Processing in the Dorsal Cochlear Nucleus—Possible Basis for Tinnitus-Related Hyperactivity?
Authors: Dehmel Susanne , Pradhan Shashwati , Koehler Seth , Bledsoe Sanford , Shore Susan
Published: February 2012

The dorsal cochlear nucleus (DCN) is the first neural site of bimodal auditory-somatosensory integration. Previous studies have shown that stimulation of somatosensory pathways results in immediate suppression or enhancement of subsequent acoustically evoked discharges. In the unimpaired auditory system suppression predominates. However, damage to the auditory input pathway leads to enhancement of excitatory somatosensory inputs to the cochlear nucleus, changing their effects on DCN neurons (Shore et al., 2008; Zeng et al., 2009).

Given the well described connection between the somatosensory system and tinnitus in patients we sought to determine whether plastic changes in long-lasting bimodal somatosensory-auditory processing accompany tinnitus. Here we demonstrate for the first timein vivolong-term effects of somatosensory inputs on acoustically evoked discharges of DCN neurons in guinea pigs. The effects of trigeminal nucleus stimulation are compared between normal-hearing animals and animals overexposed with narrow band noise and behaviorally tested for tinnitus. The noise exposure resulted in a temporary threshold shift in auditory brainstem responses but a persistent increase in spontaneous and sound-evoked DCN unit firing rates and increased steepness of rate-level functions. Rate increases were especially prominent in buildup units. The long-term somatosensory enhancement of sound-evoked responses was strengthened while suppressive effects diminished in noise-exposed animals, especially those that developed tinnitus.

Damage to the auditory nerve is postulated to trigger compensatory long-term synaptic plasticity of somatosensory inputs that might be an important underlying mechanism for tinnitus generation.
Natural versus Synthetic Stimuli for Estimating Receptive Field Models: A Comparison of Predictive Robustness
Authors: Talebi Vargha , Baker Curtis L.
Published: February 2012

An ultimate goal of visual neuroscience is to understand the neural encoding of complex, everyday scenes. Yet most of our knowledge of neuronal receptive fields has come from studies using simple artificial stimuli (e.g., bars, gratings) that may fail to reveal the full nature of a neuron's actual response properties. Our goal was to compare the utility of artificial and natural stimuli for estimating receptive field (RF) models. Using extracellular recordings from simple type cells in cat A18, we acquired responses to three types of broadband stimulus ensembles: two widely used artificial patterns (white noise and short bars), and natural images. We used a primary dataset to estimate the spatiotemporal receptive field (STRF) with two hold-back datasets for regularization and validation. STRFs were estimated using an iterative regression algorithm with regularization and subsequently fit with a zero-memory nonlinearity. Each RF model (STRF and zero-memory nonlinearity) was then used in simulations to predict responses to the same stimulus type used to estimate it, as well as to other broadband stimuli and sinewave gratings. White noise stimuli often elicited poor responses leading to noisy RF estimates, while short bars and natural image stimuli were more successful in driving A18 neurons and producing clear RF estimates with strong predictive ability. Natural image-derived RF models were the most robust at predicting responses to other broadband stimulus ensembles that were not used in their estimation and also provided good predictions of tuning curves for sinewave gratings.
μ- and δ-Opioid-Related Processes in the Accumbens Core and Shell Differentially Mediate the Influence of Reward-Guided and Stimulus-Guided Decisions on Choice
Authors: Laurent Vincent , Leung Beatrice , Maidment Nigel , Balleine Bernard W.
Published: February 2012

Two motivational processes affect choice between actions: (1) changes in the reward value of the goal or outcome of an action and (2) changes in the predicted value of an action based on outcome-related stimuli. Here, we evaluated the role of μ-opioid receptor (MOR) and δ-opioid receptor (DOR) in the nucleus accumbens in the way these motivational processes influence choice using outcome revaluation and pavlovian-instrumental transfer tests. We first examined the effect of genetic deletion of MOR and DOR in specific knock-out mice. We then assessed the effect of infusing the MOR antagonistd-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2(CTAP) or the DOR antagonist naltrindole into the core or shell subregions of the nucleus accumbens on these tests in rats. We found that, whereas MOR knock-outs showed normal transfer, they failed to show a selective outcome revaluation effect. Conversely, DOR knock-outs showed normal revaluation but were insensitive to the influence of outcome-related cues on choice. This double dissociation was also found regionally within the nucleus accumbens in rats. Infusion of naltrindole into the accumbens shell abolished transfer but had no effect on outcome revaluation and did not influence either effect when infused into the accumbens core. Conversely, infusion of CTAP into the accumbens core abolished sensitivity to outcome revaluation but had no effect on transfer and did not influence either effect when infused into the accumbens shell. These results suggest that reward-based and stimulus-based values exert distinct motivational influences on choice that can be doubly dissociated both neuroanatomically and neurochemically at the level of the nucleus accumbens.
Differentiated Participation of Thalamocortical Subnetworks in Slow/Spindle Waves and Desynchronization
Authors: Ushimaru Mika , Ueta Yoshifumi , Kawaguchi Yasuo
Published: February 2012

During sleep, the electroencephalogram exhibits synchronized slow waves that desynchronize when animals awaken [desynchronized states (DSs)]. During slow-wave states, the membrane potentials of cortical neurons oscillate between discrete depolarized states (“Up states”) and periods of hyperpolarization (“Down states”). To determine the role of corticothalamic loops in generating Up/Down oscillations in rats, we recorded unit activities of layer 5 (L5) corticothalamic (CTh) cells in the frontal cortex, neurons in the thalamic reticular nucleus, and basal ganglia- and cerebellum-linked thalamic relay nuclei, while simultaneously monitoring the local cortical field potential to identify slow-wave/spindle oscillations and desynchronization. We found that (1) some basal ganglia-linked and reticular thalamic cells fire preferentially near the beginning of Up states; (2) thalamic cells fire more selectively at a given Up-state phase than do CTh cells; (3) CTh and thalamic cells exhibit different action potential timings within spindle cycles; and (4) neurons exhibit different firing characteristics when comparing their activity during Up states and DSs. These data demonstrate that cortico-thalamo-cortical subnetworks are temporally differentiated during slow and spindle oscillations, that the basal ganglia-linked thalamic nuclei are closely related with Up-state initiation, and that Up states and DSs are distinguished as different depolarization states of neurons within the network.
Organization of Vomeronasal Sensory Coding Revealed by Fast Volumetric Calcium Imaging
Authors: Turaga Diwakar , Holy Timothy E.
Published: February 2012

A long-standing goal in neuroscience is to perform exhaustive recording of each neuron in a functional local circuit. To achieve this goal, one promising approach is optical imaging of fluorescent calcium indicators, but typically the tens or hundreds of cells imaged simultaneously comprise only a tiny percentage of the neurons in an intact circuit. Here, we show that a recent innovation, objective-coupled planar illumination (OCPI) microscopy, permits simultaneous recording from three-dimensional volumes containing many thousand neurons. We used OCPI microscopy to record chemosensory responses in the mouse vomeronasal epithelium, for which expression of hundreds of receptor types implies high functional diversity. The implications of this diversity for sensory coding were examined using several classes of previously reported vomeronasal ligands, including sulfated steroids. A collection of just 12 sulfated steroids activated more than a quarter of the neurons in the apical vomeronasal epithelium; unexpectedly, responses were functionally organized into a modest number of classes with characteristic spatial distribution. Recording from a whole sensory system thus revealed new organizational principles.
Contrast-Enhanced Magnetic Resonance Microangiography Reveals Remodeling of the Cerebral Microvasculature in Transgenic ArcAβ Mice
Authors: Klohs Jan , Baltes Christof , Princz-Kranz Felicitas , Ratering David , Nitsch Roger M. , Knuesel Irene , Rudin Markus
Published: February 2012

Amyloid-β (Aβ) deposition in the cerebral vasculature is accompanied by remodeling which has a profound influence on vascular integrity and function. In the current study we have quantitatively assessed the age-dependent changes of the cortical vasculature in the arcAβ model of cerebral amyloidosis. To estimate the density of the cortical microvasculaturein vivo, we used contrast-enhanced magnetic resonance microangiography (CE-μMRA). Three-dimensional gradient echo datasets with 60 μm isotropic resolution were acquired in 4- and 24-month-old arcAβ mice and compared with wild-type (wt) control mice of the same age before and after administration of superparamagnetic iron oxide nanoparticles. After segmentation of the cortical vasculature from difference images, an automated algorithm was applied for assessing the number and size distribution of intracortical vessels. With CE-μMRA, cerebral arteries and veins with a diameter of less than the nominal pixel resolution (60 μm) can be visualized. A significant age-dependent reduction in the number of functional intracortical microvessels (radii of 20–80 μm) has been observed in 24-month-old arcAβ mice compared with age-matched wt mice, whereas there was no difference between transgenic and wt mice of 4 months of age. Immunohistochemistry demonstrated strong fibrinogen and Aβ deposition in small- and medium-sized vessels, but not in large cerebral arteries, of 24-month-old arcAβ mice. The reduced density of transcortical vessels may thus be attributed to impaired perfusion and vascular occlusion caused by deposition of Aβ and fibrin. The study demonstrated that remodeling of the cerebrovasculature can be monitored noninvasively with CE-μMRA in mice.
5-HT1AReceptor-Responsive Pedunculopontine Tegmental Neurons Suppress REM Sleep and Respiratory Motor Activity
Authors: Grace Kevin P. , Liu Hattie , Horner Richard L.
Published: February 2012

Serotonin type 1A (5-HT1A) receptor-responsive neurons in the pedunculopontine tegmental nucleus (PPTn) become maximally active immediately before and during rapid eye movement (REM) sleep. A prevailing model of REM sleep generation indicates that activation of such neurons contributes significantly to the generation of REM sleep, and if correct then inactivation of such neurons ought to suppress REM sleep. We test this hypothesis using bilateral microperfusion of the 5-HT1Areceptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 10 μm) into the PPTn; this tool has been shown to selectively silence REM sleep-active PPTn neurons while the activity of wake/REM sleep-active PPTn neurons is unaffected. Contrary to the prevailing model, bilateral microperfusion of 8-OH-DPAT into the PPTn (n= 23 rats) significantly increased REM sleep both as a percentage of the total recording time and sleep time, compared with both within-animal vehicle controls and between-animal time-controls. This increased REM sleep resulted from an increased frequency of REM sleep bouts but not their duration, indicating an effect on mechanisms of REM sleep initiation but not maintenance. Furthermore, an increased proportion of the REM sleep bouts stemmed from periods of low REM sleep drive quantified electrographically. Targeted suppression of 5-HT1Areceptor-responsive PPTn neurons also increased respiratory rate and respiratory-related genioglossus activity, and increased the frequency and amplitude of the sporadic genioglossus activations occurring during REM sleep. These data indicate that 5-HT1Areceptor-responsive PPTn neurons normally function to restrain REM sleep by elevating the drive threshold for REM sleep induction, and restrain the expression of respiratory rate and motor activities.
Flowering Time in Maize: Linkage and Epistasis at a Major Effect Locus
Authors: Durand Eléonore , Bouchet Sophie , Bertin Pascal , Ressayre Adrienne , Jamin Philippe , Charcosset Alain , Dillmann Christine , Tenaillon Maud I
Published: February 2012

In a previous study, we identified a candidate fragment length polymorphism associated with flowering time variation after seven generations of selection for flowering time, starting from the maize inbred line F252. Here, we characterized the candidate region and identified underlying polymorphisms. Then, we combined QTL mapping, association mapping, and developmental characterization to dissect the genetic mechanisms responsible for the phenotypic variation. The candidate region contained the Eukaryotic Initiation Factor (eIF-4A) and revealed a high level of sequence and structural variation beyond the 3′-UTR of eIF-4A, including several insertions of truncated transposable elements. Using a biallelic single-nucleotide polymorphism (SNP) (C/T) in the candidate region, we confirmed its association with flowering time variation in a panel of 317 maize inbred lines. However, while the T allele was correlated with late flowering time within the F252 genetic background, it was correlated with early flowering time in the association panel with pervasive interactions between allelic variation and the genetic background, pointing to underlying epistasis. We also detected pleiotropic effects of the candidate polymorphism on various traits including flowering time, plant height, and leaf number. Finally, we were able to break down the correlation between flowering time and leaf number in the progeny of a heterozygote (C/T) within the F252 background consistent with causal loci in linkage disequilibrium. We therefore propose that both a cluster of tightly linked genes and epistasis contribute to the phenotypic variation for flowering time.