bluuebunny/crossref_metadata_2025 huggingface dataset:
The development and application of new crystallization method for tobacco mosaic virus coat protein
Authors: Li Xiangyang , Song Baoan , Hu Deyu , Wang Zhenchao , Zeng Mengjiao , Yu Dandan , Chen Zhuo , Jin Linhong , Yang Song
Published: November 2012

Background

Although tobacco mosaic virus (TMV) coat protein (CP) has been isolated from virus particles and its crystals have grown in ammonium sulfate buffers for many years, to date, no one has reported on the crystallization of recombinant TMV-CP connecting peptides expressed in E. coli.

Methods

In the present papers genetically engineered TMV-CP was expressed, into which hexahistidine (His) tags or glutathione-S-transferase (GST) tags were incorporated. Considering that GST-tags are long peptides and His-tags are short peptides, an attempt was made to grow crystals of TMV-CP cleaved GST-tags (WT-TMV-CP32) and TMV-CP incorporated His-tags (WT-His-TMV-CP12) simultaneously in ammonium sulfate buffers and commercial crystallization reagents. It was found that the 20S disk form of WT-TMV-CP32 and WT-His-TMV-CP12 did not form high resolution crystals by using various crystallization buffers and commercial crystallization reagents. Subsequently, a new experimental method was adopted in which a range of truncated TMV-CP was constructed by removing several amino acids from the N- or the C-terminal, and high resolution crystals were grown in ammonium sulfate buffers and commercial crystallization reagents.

Results

The new crystallization method was developed and 3.0 Å resolution macromolecular crystal was thereby obtained by removing four amino acids at the C-terminal of His-TMV-CP and connecting six His-tags at the N-terminal of His-TMV-CP (TR-His-TMV-CP19). The Four-layer aggregate disk structure of TR-His-TMV-CP19 was solved. This phenomenon showed that peptides at the C-terminus hindered the growth of high resolution crystals and the peptides interactions at the N-terminus were attributed to the quality of TMV-CP crystals.

Conclusion

A 3.0 Å resolution macromolecular crystal of TR-His-TMV-CP19 was obtained and the corresponding structure was solved by removing four amino acids at the C-terminus of TMV-CP and connecting His-tags at the N-terminus of TMV-CP. It indicated that short peptides influenced the resolution of TMV-CP crystals.
Replication kinetics of duck enteritis virus UL16 gene in vitro
Authors: He Qin , Cheng Anchun , Wang Mingshu , Xiang Jun , Zhu Dekang , Zhou Yi , Jia Renyong , Chen Shun , Chen Zhengli , Chen Xiaoyue
Published: November 2012

Background

The function and kinetics of some herpsvirus UL16 gene have been reported. But there was no any report of duck enteritis virus (DEV) UL16 gene.

Findings

The kinetics of DEV UL16 gene was examined in DEV CHv infected duck embryo fibroblasts (DEFs) by establishment of real-time quantitative reverse transcription polymerase chain reaction assay (qRT-PCR) and western-blotting. In this study, UL16 mRNA was transcript at a low level from 0–18 h post-infection (p.i), and peaked at 36 h p.i. It can’t be detected in the presence of acyclovir (ACV). Besides, western-blotting analysis showed that UL16 gene expressed as an apparent 40-KDa in DEV infected cell lysate from 12 h p.i, and rose to peak level at 48 h p.i consistent with the qRT-PCR result.

Conclusions

These results provided the first evidence of the kinetics of DEV UL16 gene. DEV UL16 gene was a late gene and dependent on viral DNA synthesis.
Practice effects in a longitudinal, multi-center Alzheimer’s disease prevention clinical trial
Authors: Abner Erin L , Dennis Brandon C , Mathews Melissa J , Mendiondo Marta S , Caban-Holt Allison , Kryscio Richard J , Schmitt Frederick A ,   for the PREADViSE Investigators, Crowley John J ,   for the SELECT Investigators
Published: November 2012

Background

Practice effects are a known threat to reliability and validity in clinical trials. Few studies have investigated the potential influence of practice on repeated screening measures in longitudinal clinical trials with a focus on dementia prevention. The current study investigates whether practice effects exist on a screening measure commonly used in aging research, the Memory Impairment Screen (MIS).

Methods

The PREADViSE trial is a clinical intervention study evaluating the efficacy of vitamin E and selenium for Alzheimer’s disease prevention. Participants are screened annually for incident dementia with the MIS. Participants with baseline and three consecutive follow-ups who made less than a perfect score at one or more assessments were included in the current analyses (N=1,803). An additional subset of participants with four consecutive assessments but who received the same version of the MIS at baseline and first follow-up (N=301) was also assessed to determine the effects of alternate forms on mitigating practice. We hypothesized that despite efforts to mitigate practice effects with alternate versions, MIS scores would improve with repeated screening. Linear mixed models were used to estimate mean MIS scores over time.

Results

Among men with four visits and alternating MIS versions, although there is little evidence of a significant practice effect at the first follow-up, mean scores clearly improve at the second and third follow-ups for all but the oldest participants. Unlike those who received alternate versions, men given the same version at first follow-up show significant practice effects.

Conclusion

While increases in the overall means were small, they represent a significant number of men whose scores improved with repeated testing. Such improvements could bias case ascertainment if not taken into account.
Characteristics of the Colombian armed conflict and the mental health of civilians living in active conflict zones
Authors: Bell Vaughan , Méndez Fernanda , Martínez Carmen , Palma Pedro Pablo , Bosch Marc
Published: November 2012

Background

Despite the fact that the Colombian armed conflict has continued for almost five decades there is still very little information on how it affects the mental health of civilians. Although it is well established in post-conflict populations that experience of organised violence has a negative impact on mental health, little research has been done on those living in active conflict zones. Médecins Sans Frontières provides mental health services in areas of active conflict in Colombia and using data from these services we aimed to establish which characteristics of the conflict are most associated with specific symptoms of mental ill health.

Methods

An analysis of clinical data from patients (N = 6,353), 16 years and over, from 2010–2011, who consulted in the Colombian departments (equivalent to states) of Nariño, Cauca, Putumayo and Caquetá. Risk factors were grouped using a hierarchical cluster analysis and the clusters were included with demographic information as predictors in logistic regressions to discern which risk factor clusters best predicted specific symptoms.

Results

Three clear risk factor clusters emerged which were interpreted as ‘direct conflict related violence’, ‘personal violence not directly conflict-related’ and ‘general hardship’. The regression analyses indicated that conflict related violence was more highly related to anxiety-related psychopathology than other risk factor groupings while non-conflict violence was more related to aggression and substance abuse, which was more common in males. Depression and suicide risk were represented equally across risk factor clusters.

Conclusions

As the largest study of its kind in Colombia it demonstrates a clear impact of the conflict on mental health. Among those who consulted with mental health professionals, specific conflict characteristics could predict symptom profiles. However, some of the highest risk outcomes, like depression, suicide risk and aggression, were more related to factors indirectly related to the conflict. This suggests a need to focus on the systemic affects of armed conflict and not solely on direct exposure to fighting.
Acquired urethral diverticulum in a man with paraplegia presenting with a scrotal mass: a case report
Authors: El Ammari Jalal Eddine , Riyach Omar , Ahsaini Mustapha , Ahallal Youness , El Fassi Mohammed Jamal , Farih My Hassan
Published: November 2012

Introduction

Male urethral diverticula are rare. Patients with paraplegia may present with acquired diverticula as a result of prolonged catheterization. Diverticula may be asymptomatic or lead to lower urinary tract symptoms. Rarely, the diverticulum may initially present as a scrotal mass.

Case presentation

We report the case of a male 45-year-old Arab with paraplegia who presented with a mass in the peno-scrotal junction. He had in his medical history iterative prolonged urethral catheterizations associated with urine leakage through the urethral meatus upon applying compression. Diagnosis confirmation of urethral diverticula is obtained by retrograde urethrography. The patient underwent a diverticulectomy with urethroplasty.

Conclusion

Male acquired urethral diverticula can be found in patients who have a spinal cord injury because of prolonged urethral catheterization. Clinical presentations are different and sometimes can be misleading. Retrograde urethrography is the key to diagnosis and open surgery is the treatment of reference.
Application of RNA silencing to plant disease resistance
Authors: Duan Cheng-Guo , Wang Chun-Han , Guo Hui-Shan
Published: November 2012

To reduce the losses caused by plant pathogens, plant biologists have adopted numerous methods to engineer resistant plants. Among them, RNA silencing-based resistance has been a powerful tool that has been used to engineer resistant crops during the last two decades. Based on this mechanism, diverse approaches were developed. In this review, we focus on the application of RNA silencing to produce plants that are resistant to plant viruses such as RNA and DNA viruses, viroids, insects, and the recent expansion to fungal pathogens.
Traction esophageal diverticulum: a rare cause of gastro-intestinal bleeding
Authors: Ballehaninna Umashankar K , Shaw Jason P , Brichkov Igor
Published: November 2012

Esophageal diverticula are uncommon lesions that are usually classified according to their location (cervical, thoracic, or epiphrenic), or underlying pathogenesis (pulsion or traction), and their morphology (true or false).The majority of esophageal diverticula are acquired lesions that occur predominantly in elderly adults. Pulsion, or false, diverticula are the most commonly encountered type of esophageal diverticula noticed at the level of cricopharyngeus muscle, occur as a localized outpouchings that lacks a muscular coat, and as such their wall is formed entirely by mucosa and submucosa.

True, or traction, esophageal diverticulum (TED) is seen in the middle one third of the thoracic esophagus in a peribronchial location, occurs secondary to mediastinal inflammatory lesions such as tuberculosis or histoplasmosis. The resultant desmoplastic reaction in the paraesophageal tissue causes full thickness pinching on the esophageal wall, producing a conical, broad-mouthed true diverticulum. They often project to the right side because subcarinal lymph nodes in this area are closely associated with the right anterior wall of the esophagus.

TED usually presents with symptoms such as dysphagia, postural regurgitation, belching, retrosternal pain, heartburn, and epigastric pain. As in patients with pharyngoesophageal (Zenker’s) diverticula, pulmonary symptoms are often present but underestimated in TED patients. These symptoms range from mild nocturnal cough to life-threatening massive aspiration. In this particular report we describe a rare case of TED presenting as a symptomatic upper gastrointestinal bleeding. Diagnostic evaluation of TED includes chest X-ray, barium esophagogram and manometry. A significant proportion of lower esophageal diverticula are associated with motility disorders. Management of TED include treating the underlying cause sometimes a surgical resection of diverticulum along with esophageal myotomy is necessitated in symptomatic patients.
“Well, What Socks Is Pynchon Wearing Today?” A Freiburg Scrapbook in Memory of Friedrich Kittler
Authors: Winthrop-Young Geoffrey
Published: November 2012

This essay, a sequence of short memories and reflections, describes several encounters with Friedrich Kittler in Freiburg between 1980 and 1985.
Excursions and Recursions: Kittler's Homeric Wake
Authors: Powell Larson
Published: November 2012

This article is a commentary on Friedrich Kittler's “In the Wake of the Odyssey.” Kittler reads Homer as a cultural-technological program for later historical development and finds later authors such as Virgil and Dante inferior to Homer. Kittler's “Wake” rehearses on a smaller scale arguments made in his late work Music and Mathematics. His work is seen as determined by two movements of excursion, going out to the exotic, whether North American or Mediterranean, and recursion, meaning the closure of mathematical or logical systems. Yet recursion, in Kittler, turns out to be more a rhetorical figure than a function.
A Predictably Obedient Riot: Postpolitics, Consumer Culture, and the English Riots of 2011
Authors: Winlow Simon , Hall Steve
Published: November 2012

In this article we attempt to develop an analysis of the English urban riots of 2011. Rather than build on the assumption of organic resistance and protopolitics, we argue that the disturbances were a brief eruption of social unrest that lacked the clear, unifying political symbolism necessary to turn objectless dissatisfaction into articulate political demands. Rather, the consumer-oriented subjects who inhabit the socioeconomic margins of late capitalism were unable to make this political move and ultimately found themselves with nowhere to take their dissatisfaction but to the shops. This speaks loudly of the current condition of subjectivity in a postpolitical era dominated by neoliberalism and liberal postmodernism.
Sonar jamming in the field: effectiveness and behavior of a unique prey defense
Authors: Corcoran Aaron J. , Conner William E.
Published: November 2012

Bats and insects provide a model system for integrating our understanding of predator–prey ecology, animal behavior and neurophysiology. Previous field studies of bat–insect interactions have been limited by the technological challenges involved with studying nocturnal, volant animals that use ultrasound and engage in battles that frequently last a fraction of a second. We overcame these challenges using a robust field methodology that included multiple infrared cameras calibrated for three-dimensional reconstruction of bat and moth flight trajectories and four ultrasonic microphones that provided a spatial component to audio recordings. Our objectives were to document bat–moth interactions in a natural setting and to test the effectiveness of a unique prey defense – sonar jamming. We tested the effect of sonar jamming by comparing the results of interactions between bats and Grote’s tiger moth, Bertholdia trigona, with their sound-producing organs either intact or ablated. Jamming was highly effective, with bats capturing more than 10 times as many silenced moths as clicking moths. Moths frequently combined their acoustic defense with two separate evasive maneuvers: flying away from the bat and diving. Diving decreased bat capture success for both clicking and silenced moths, while flying away did not. The diving showed a strong directional component, a first for insect defensive maneuvers. We discuss the timing of B. trigona defensive maneuvers – which differs from that of other moths – in the context of moth auditory neuroethology. Studying bat–insect interactions in their natural environment provides valuable information that complements work conducted in more controlled settings.
Systematic evaluation of medium-throughput mRNA abundance platforms
Authors: Prokopec Stephenie D. , Watson John D. , Waggott Daryl M. , Smith Ashley B. , Wu Alexander H. , Okey Allan B. , Pohjanvirta Raimo , Boutros Paul C.
Published: November 2012

Profiling of mRNA abundances with high-throughput platforms such as microarrays and RNA-seq has become an important tool in both basic and biomedical research. However, these platforms remain prone to systematic errors and have challenges in clinical and industrial applications. As a result, it is standard practice to validate a subset of key results using alternate technologies. Similarly, clinical and industrial applications typically involve transitions from a high-throughput discovery platform to medium-throughput validation ones. These medium-throughput validation platforms have high technical reproducibility and reduced sample input needs, and low sensitivity to sample quality (e.g., for processing FFPE specimens). Unfortunately, while medium-throughput platforms have proliferated, there are no comprehensive comparisons of them. Here we fill that gap by comparing two key medium-throughput platforms—NanoString's nCounter Analysis System and ABI's OpenArray System—to gold-standard quantitative real-time RT-PCR. We quantified 38 genes and positive and negative controls in 165 samples. Signal:noise ratios, correlations, dynamic range, and detection accuracy were compared across platforms. All three measurement technologies showed good concordance, but with divergent price/time/sensitivity trade-offs. This study provides the first detailed comparison of medium-throughput RNA quantification platforms and provides a template and a standard data set for the evaluation of additional technologies.
Valuing Changes in Investment Opportunities
Authors: Abbas Ali E.
Published: November 2012

Arrow and Pratt introduced a measure of risk aversion—the negative ratio of the second to the first derivative of the utility function. This measure has found widespread use in the valuation of uncertain lotteries and in the calculation of the risk premium of an investment. This paper introduces two new measures for characterizing changes in the valuation of uncertain lotteries when their outcomes are modified by a monotone transformation. The first is a characteristic transformation of a utility function, U, and a monotone transformation, g. The shape of the characteristic transformation determines an upper bound, lower bound, or equality on the magnitude of the certainty equivalent of the modified lottery. The second is a measure of change in certainty equivalent, ηg, whose sign also determines upper or lower bounds, and whose magnitude determines the change in value of a “small-risk” lottery when its outcomes are modified by a monotone transformation. For shift (and scale) transformations on the lottery outcomes, both the characteristic transformation and the measure of change, ηg, provide new characterizations for the notions of decreasing absolute (and relative) risk aversion with wealth.
Computing Optimal Recovery Policies for Financial Markets
Authors: Benth Fred E. , Dahl Geir , Mannino Carlo
Published: November 2012

The current financial crisis motivates the study of correlated defaults in financial systems. In this paper we focus on such a model, which is based on Markov random fields. This is a probabilistic model in which uncertainty in default probabilities incorporates experts' opinions on the default risk (based on various credit ratings). We consider a bilevel optimization model for finding an optimal recovery policy: which companies should be supported given a fixed budget. This is closely linked to the problem of finding a maximum likelihood estimator of the defaulting set of agents, and we show how to compute this solution efficiently using combinatorial methods. We also prove properties of such optimal solutions and give a practical procedure for estimation of model parameters. Computational examples are presented, and experiments indicate that our methods can find optimal recovery policies for up to about 100 companies. The overall approach is evaluated on a real-world problem concerning the major banks in Scandinavia and public loans. To our knowledge, this is a first attempt to apply combinatorial optimization techniques to this important and expanding area of default risk analysis.
Congestion-Based Lead-Time Quotation for Heterogenous Customers with Convex-Concave Delay Costs: Optimality of a Cost-Balancing Policy Based on Convex Hull Functions
Authors: Akan Mustafa , Ata Barı ş , Olsen Tava
Published: November 2012

We consider a congestible system serving multiple classes of customers who differ in their delay sensitivity and valuation of service (or product). Customers are endowed with convex-concave delay cost functions. A system manager offers a menu of lead times and corresponding prices to arriving customers, who then choose the lead-time–price pair that maximizes their net utility (value minus disutility of delay and price). We investigate how such menus should be chosen dynamically (depending on the system backlog) to maximize welfare. We formulate a novel fluid model of the problem and show that the cost-balancing policy (based on the convex hulls of the delay cost functions) is socially optimal if the system manager can tell customer types apart. If types are indistinguishable to the system manager, the cost-balancing policy is also incentive compatible under social optimization. Finally, we show through a simulation study that the cost-balancing policy does well in the context of the original (stochastic) problem by testing it against various natural benchmarks.
Concomitant Use of Ipratropium and Tiotropium in Chronic Obstructive Pulmonary Disease
Authors: Cole Jennifer M , Sheehan Amy Heck , Jordan Joseph K
Published: November 2012

Objective:

To describe the current data evaluating the efficacy and safety of ipratropium used in combination with tiotropium in patients with chronic obstructive pulmonary disease.

Data Sources:

A literature search using MEDLINE (1966-August 2012) and EMBASE (1973-August 2012) was conducted using the search terms ipratropium, tiotropium, combination drug therapy, and chronic obstructive pulmonary disease. References of identified articles were reviewed for additional relevant citations.

Study Selection and Data Extraction:

All English-language articles regarding the concomitant use of ipratropium and tiotropium were reviewed.

Data Synthesis:

Two prospective randomized controlled trials have demonstrated increases in bronchodilation with ipratropium when added to maintenance tiotropium therapy, suggesting potential benefits during short-term, combined use. One study reported significantly higher peak forced expiratory volume in 1 second (FEV,) responses with both ipratropium (230 mL) and fenoterol (315 mL) compared to placebo (178 mL) when added to maintenance tiotropium. The peak response with fenoterol was significantly higher than with ipratropium (FEV, difference = 84 mL). Another study reported a mean difference in FEV, of 81 mL (95% CI 27 to 136) with albuterol versus placebo and a mean difference in FEV, of 68 mL (95% CI 3 to 132) with ipratropium versus placebo. The difference between albuterol and ipratropium when added to maintenance tiotropium was not significant. One large observational study reported a significantly higher risk of acute urinary retention in individuals receiving combination therapy with a short- and long-acting anticholinergic agent compared to those receiving monotherapy (OR 1.84; 95% CI 1.25 to 2.71). Individuals at highest risk were men and those with evidence of benign prostatic hypertrophy.

Conclusions:

While ipratropium may provide spirometric improvements in lung function for patients receiving tiotropium maintenance therapy, the clinical significance of these improvements has not been documented and the risk of anticholinergic adverse effects is increased with combination therapy. Further studies evaluating the safety and efficacy of concomitant ipratropium and tiotropium are warranted before combination use can be recommended for select patients.
Effectiveness of Palonosetron Versus Other Serotonin 5-HT3 Receptor Antagonists in Triple Antiemetic Regimens During Multiday Highly Emetogenic Chemotherapy
Authors: Kim Kyung Im , Lee Dong Eun , Cho Inhye , Yoon Jeong-Hyun , Yoon Sung-Soo , Lee Hye Suk , Oh Jung Mi
Published: November 2012

Background:

The second-generation serotonin 5-HT3 receptor antagonist palonosetron has shown improved efficacy in the prevention of both acute and delayed chemotherapy-induced nausea and vomiting (CINV). However, there have been no randomized controlled trials supporting the preferential use of palonosetron in triple antiemetic regimens for patients receiving multiday highly emetogenic chemotherapy (HEC).

Objective:

To compare the effectiveness of palonosetron-based and first-generation 5-HT3 receptor antagonist–based triple antiemetic regimens in cancer patients receiving multiday HEC.

Methods:

This was a review and analysis of medical record data. A total of 115 patients who had received multiday HEC were included and grouped into a palonosetron-based antiemetic group (n = 73) or a first-generation 5-HT3 receptor antagonist–based antiemetic group (n = 42). Data on CINV were collected in 24-hour intervals for 120 hours after the start of chemotherapy.

Results:

Complete response rates did not differ significantly between the 2 groups during any of the 3 phases: acute (0-24 hours), p = 0.877; overlap (24-120 hours), p = 0.997; and overall (0-120 hours), p = 0.723. The proportion of patients with complete control was similar between the groups during each phase: acute, p = 0.862; overlap, p = 0.838; and overall, p = 0.828. There was also no significant difference in other end points between the 2 groups. Among all patients, females experienced significantly more acute nausea (p = 0.040) and vomiting (p = 0.046) than males. Compared with nondrinkers, patients who consumed alcohol had a lower overall incidence of vomiting (p = 0.020).

Conclusions:

Within a triple antiemetic regimen, a palonosetron-based antiemetic regimen was not significantly different from regimens based on first-generation 5-HT3 receptor antagonists in preventing CINV during multiday HEC.
Prescription-Acquired Acetaminophen Use and the Risk of Asthma in Adults: A Case-Control Study
Authors: Kelkar Mugdha , Cleves Mario A , Foster Howell R , Hogan William R , James Laura P , Martin Bradley C
Published: November 2012

Background:

Studies have examined the association between acetaminophen use and asthma; however, their interpretation is limited by several methodologic issues.

Objective:

To investigate the association between recent and chronic prescription-acquired acetaminophen use and asthma.

Methods:

This retrospective case-control study used a 10% random sample of the IMS LifeLink commercial claims data from 1997 to 2009. Cases had to have at least 1 incident claim of asthma; 3:1 controls matched on age, sex, and region were randomly chosen. Acetaminophen exposure, dose, and duration were measured in the 7- and 30-day (recent) and the 1-year (chronic) look-back periods. Multivariable conditional logistic regression was used to estimate the risk of asthma associated with acetaminophen use adjusted for comorbidities, other drugs increasing asthma risk, and health system factors.

Results:

There were 28,892 cases and 86,676 controls, with mean age of 42.8 years; 37.7% were mates, and 22.6% of cases and 18.2% of controls had acetaminophen exposure in the pre-index year, with mean cumulative doses of 78.7 g and 59.8 g, respectively. There was no significant association between recent prescription acetaminophen exposure and asthma (7 days: OR 1.02, p = 0.74; 30 days: OR 0.97, p = 0.38). Cumulative prescription acetaminophen dose in the year prior increased asthma risk compared to acetaminophen nonusers (≤1 kg: OR 1.09, p < 0.001 and >1 kg: OR = 1.60, p = 0.02). Duration of prescription acetaminophen use greater than 30 days was associated with elevated asthma risk (OR 1.39, p < 0.001).

Conclusions:

Chronic prescription-acquired acetaminophen use was associated with an increased risk of asthma, while recent use was not. However, over-the-counter acetaminophen use was not captured in this study and further epidemiologic research with complete acetaminophen exposure ascertainment and research on pathophysiologic mechanisms is needed to confirm these relationships.
Very Low PSA Concentrations and Deletions of the KLK3 Gene
Authors: Rodriguez Santiago , Al-Ghamdi Osama A , Burrows Kimberley , Guthrie Philip AI , Lane J Athene , Davis Michael , Marsden Gemma , Alharbi Khalid K , Cox Angela , Hamdy Freddie C , Neal David E , Donovan Jenny L , Day Ian NM
Published: November 2012

BACKGROUND

Prostate-specific antigen (PSA), a widely used biomarker for prostate cancer (PCa), is encoded by a kallikrein gene (KLK3, kallikrein-related peptidase 3). Serum PSA concentrations vary in the population, with PCa patients generally showing higher PSA concentrations than control individuals, although a small proportion of individuals in the population display very low PSA concentrations. We hypothesized that very low PSA concentrations might reflect gene-inactivating mutations in KLK3 that lead to abnormally reduced gene expression.

METHODS

We have sequenced all KLK3 exons and the promoter and searched for gross deletions or duplications in KLK3 in the 30 individuals with the lowest observed PSA concentrations in a sample of approximately 85 000 men from the Prostate Testing for Cancer and Treatment (ProtecT) study. The ProtecT study examines a community-based population of men from across the UK with little prior PSA testing.

RESULTS

We observed no stop codons or frameshift mutations, but we did find 30 single-base genetic variants, including 3 variants not described previously. These variants included missense variants that could be functionally inactivating and splicing variants. At this stage, however, we cannot confidently conclude whether these variants markedly lower PSA concentration or activity. More importantly, we identified 3 individuals with different large heterozygous deletions that encompass all KLK3 exons. The absence of a functional copy of KLK3 in these individuals is consistent with their reduced serum PSA concentrations.

CONCLUSIONS

The clinical interpretation of the PSA test for individuals with KLK3 gene inactivation could lead to false-negative PSA findings used for screening, diagnosis, or monitoring of PCa.
The health and safety of the fine arts: Austerity, politeness and litigation culture
Authors: Ventrella Francesco
Published: November 2012

By looking at an episode of censorship of a student’s artwork dealing with explicit visualizations and naming of sex, this article discusses the relationship between austerity measures and the spread of litigation culture in current academic life. My aim is not to defend the artwork,
but to understand how the institutional ‘straight mind’, operating for the health of public morality, may become a threat to the safety of art teaching in times of austerity. Jacques Rancière’s elaborations on the stultification of contemporary culture provide a theoretical
framework to show how litigation culture is an effect of austerity measures, which, by pre-empting any space for intellectual disagreement, may erode the relationship between education and citizenship.
New progressive architecture: Designing for cities in end times
Authors: Nawratek Krzysztof
Published: November 2012

Alongside investment banks and bankers, architecture and architects should be blamed for the global economic crisis that hit cities in 2008. Risky financial speculations were driven by a real estate bubble that relied on the production of spectacular, expensive buildings by the architecture
industry. Four years later, contemporary architecture (especially in Europe) still fails to engage with or promote socially aware, progressive urban thinking. The tradition of socially engaged architecture has almost vanished. That attitude is apparent only in remnant form – small initiatives
focused on buildings rather than on the built environment as a whole. Our new cities of austerity require a reassessment of this attitude, and a fresh generation of architects must be educated to address the challenges facing our urban environment.This article presents a theoretical framework
of a new paradigm of radical architecture and radical architecture education, as a function of strong social and political positions taken by students. This framework is the current result of three years of work conducted at the M.Arch. programme at the University of Plymouth, United Kingdom,
including projects from 2009 to 2012: one in Riga, Latvia, the second in Gdansk, Poland and the most recent in Zielona Góra, Poland. It will illustrate how architecture and urban design could become a tool for social and political change and a means to create liveable cities from the
ruins of the neo-liberal model.
Task-Relevant and Accessory Items in Working Memory Have Opposite Effects on Activity in Extrastriate Cortex
Authors: Peters Judith C. , Roelfsema Pieter R. , Goebel Rainer
Published: November 2012

During visual search, the working memory (WM) representation of the search target guides attention to matching items in the visual scene. However, we can hold multiple items in WM. Do all these items guide attention at the same time? Using a new functional magnetic resonance imaging visual search paradigm, we found that items in WM can attain two different states that influence activity in extrastriate visual cortex in opposite directions: whereas the target item in WM enhanced processing of matching visual input, other “accessory” items in memory suppressed activity. These results imply that the representation of task-relevant and (currently) task-irrelevant representations in WM differs, revealing new insights into the organization of human visual WM. The suppressive influence of irrelevant WM items may complement the attention-guiding influence of task-relevant WM items, helping us to focus on task-relevant information without getting distracted by irrelevant memory content.
Dopamine Precursor Depletion Impairs Timing in Healthy Volunteers by Attenuating Activity in Putamen and Supplementary Motor Area
Authors: Coull Jennifer T. , Hwang Hye J. , Leyton Marco , Dagher Alain
Published: November 2012

Neuropsychological investigations of patients with Parkinson's disease, schizophrenia, or attention deficit disorder converge with psychopharmacological studies in animals and healthy volunteers to implicate dopamine (DA) pathways in timing. In parallel, single-cell recording and functional neuroimaging studies have highlighted the importance of basal ganglia, prefrontal cortex, and supplementary motor area (SMA) for timing. In a placebo-controlled, within-subject design, we combined event-related functional magnetic resonance imaging with a DA manipulation (acute phenylalanine/tyrosine depletion; APTD) in healthy volunteers to pinpoint the neuroanatomical and functional substrates of the DA modulation of timing. Behaviorally, APTD selectively impaired accuracy of perceptual timing, with no effect on performance of a color-control task matched for difficulty, working memory (WM), and attentional demands. Neurally, APTD attenuated timing-specific activity in the putamen and SMA. Notably, APTD-induced decreases in brain activity were directly correlated to APTD-induced impairments in timing performance. Moreover, APTD modulated timing-specific activity selectively during initial storage of the sample duration, but had no effect during its subsequent retrieval or comparison to a probe. Our results do not simply reflect DA modulation of WM since the color task controlled for the WM updating process necessary for timing of durations in the seconds range. Moreover, preliminary evidence indicated APTD effects on putamen and SMA were greater for subsecond (540 ms) than suprasecond (1080 ms) durations, when WM demands would actually be lower. Instead, we show for the first time in healthy humans that DA manipulation perturbs timing by attenuating the activity in putamen and SMA that mediates initial storage of temporal information into WM.
NMDA Receptor-Dependent Afterdepolarizations Are Curtailed by Carbonic Anhydrase 14: Regulation of a Short-Term Postsynaptic Potentiation
Authors: Makani Sachin , Chen Huei-Ying , Esquenazi Susana , Shah Gul N. , Waheed Abdul , Sly William S. , Chesler Mitchell
Published: November 2012

In the hippocampus, extracellular carbonic anhydrase (Car) speeds the buffering of an activity-generated rise in extracellular pH that impacts H+-sensitive NMDA receptors (NMDARs). We studied the role of Car14 in this brain structure, in which it is expressed solely on neurons. Current-clamp responses were recorded from CA1 pyramidal neurons in wild-type (WT) versus Car14 knock-out (KO) mice 2 s before (control) and after (test) a 10 pulse, 100 Hz afferent train. In both WT and KO, the half-width (HW) of the test response, and its number of spikes, were augmented relative to the control. An increase in presynaptic release was not involved, because AMPAR-mediated EPSCs were depressed after a train. The increases in HW and spike number were both greater in the Car14 KO. In 0 Mg2+saline with picrotoxin (using a 20 Hz train), the HW measures were still greater in the KO. The Car inhibitor benzolamide (BZ) enhanced the test response HW in the WT but had no effect on the already-prolonged HW in the KO. With intracellular MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]-cyclohepten-5,10-imine maleate], the curtailed WT and KO responses were indistinguishable, and BZ caused no change. In contrast, the extracellular alkaline changes evoked by the train were not different between WT and KO, and BZ amplified these alkalinizations similarly. These data suggest that Car14 regulates pH transients in the perisynaptic microenvironment and govern their impact on NMDARs but plays little role in buffering pH shifts in the broader, macroscopic, extracellular space.
The Complex PrPc-Fyn Couples Human Oligomeric Aβ with Pathological Tau Changes in Alzheimer's Disease
Authors: Larson Megan , Sherman Mathew A. , Amar Fatou , Nuvolone Mario , Schneider Julie A. , Bennett David A. , Aguzzi Adriano , Lesné Sylvain E.
Published: November 2012

Amid controversy, the cellular form of the prion protein PrPchas been proposed to mediate oligomeric amyloid-β (Aβ)-induced deficits. In contrast, there is consistent evidence that the Src kinase Fyn is activated by Aβ oligomers and leads to synaptic and cognitive impairment in transgenic animals. However, the molecular mechanism by which soluble Aβ activates Fyn remains unknown. Combining the use of human and transgenic mouse brain tissue as well as primary cortical neurons, we demonstrate that soluble Aβ binds to PrPcat neuronal dendritic spinesin vivoandin vitrowhere it forms a complex with Fyn, resulting in the activation of the kinase. Using the antibody 6D11 to prevent oligomeric Aβ from binding to PrPc, we abolished Fyn activation and Fyn-dependent tau hyperphosphorylation induced by endogenous oligomeric Aβin vitro. Finally, we showed that gene dosage ofPrnpregulates Aβ-induced Fyn/tau alterations. Together, our findings identify a complete signaling cascade linking one specific endogenous Aβ oligomer, Fyn alteration, and tau hyperphosphorylation in cellular and animal models modeling aspects of the molecular pathogenesis of Alzheimer's disease.
The Lateral Hypothalamic Area Controls Paradoxical (REM) Sleep by Means of Descending Projections to Brainstem GABAergic Neurons
Authors: Clément Olivier , Sapin Emilie , Libourel Paul-Antoine , Arthaud Sébastien , Brischoux Frédéric , Fort Patrice , Luppi Pierre-Hervé
Published: November 2012

It has recently been shown that the ventrolateral part of the periaqueductal gray (VLPAG) and the adjacent dorsal deep mesencephalic nucleus (dDpMe) contain GABAergic neurons gating paradoxical sleep (PS) onset by means of their projection to the glutamatergic PS-on neurons of the sublaterodorsal tegmental nucleus (SLD). To determine the mechanisms responsible for the cessation of activity of these GABAergic PS-off neurons at the onset and during PS, we combined the immunostaining of c-FOS, a marker of neuronal activation, with cholera toxin b subunit (CTb) retrograde tracing from the VLPAG/dDpMe in three groups of rats (control, PS deprived, and PS hypersomniac). We found that the lateral hypothalamic area (LH) is the only brain structure containing a very large number of neurons activated during PS hypersomnia and projecting to the VLPAG/dDpMe. We further demonstrated that 44% of these neurons express the neuropeptide melanin concentrating hormone (MCH). We then showed that bilateral injections in the LH of two inhibitory compounds, clonidine (an α-2 adrenergic agonist) and muscimol (a GABAa agonist) induce an inhibition of PS. Furthermore, after muscimol injections in the LH, the VLPAG/dDpMe contained a large number of activated neurons, mostly GABAergic, and projecting to the SLD. Altogether, our results indicate for the first time that the activation of a population of LH neurons, in part MCH containing, is necessary for PS to occur. Furthermore, our results strongly suggest that these neurons trigger PS by means of their inhibitory projection to the PS-off GABAergic neurons located in the VLPAG/dDpMe.
Enhanced GABAergic Activity in the Mouse Primary Somatosensory Cortex Is Insufficient to Alleviate Chronic Pain Behavior with Reduced Expression of Neuronal Potassium–Chloride Cotransporter
Authors: Eto Kei , Ishibashi Hitoshi , Yoshimura Takeshi , Watanabe Miho , Miyamoto Akiko , Ikenaka Kazuhiro , Moorhouse Andrew J. , Nabekura Junichi
Published: November 2012

The correct balance between excitation and inhibition is crucial for brain function and disrupted in several pathological conditions. Excitatory neuronal circuits in the primary somatosensory cortex (S1) are modulated by local inhibitory neurons with the balance of this excitatory and inhibitory activity important for function. The activity of excitatory layer 2/3 neurons (L2/3) in the S1 cortex is increased in chronic pain, but it is not known how the local interneurons, nor the balance between excitation and inhibition, may change in chronic pain. Usingin vivotwo-photon calcium imaging and electrophysiology, we report here that the response of L2/3 local inhibitory neurons to both sensory stimulation and to layer 4 electrical stimulation increases in inflammatory chronic pain. Local application into L2/3 of a GABAAreceptor blocker further enhanced the activity of S1 excitatory neurons and reduced pain thresholds, whereas local application of the GABAAreceptor modulators (muscimol and diazepam) transiently alleviated the allodynia. This illustrates the importance of the local inhibitory pathways in chronic pain sensation. A reduction in the expression and function of the potassium–chloride cotransporter 2 occurred during chronic pain, which reduces the efficacy of the inhibitory inputs to L2/3 excitatory neurons. In summary, both excitatory and inhibitory neuronal activities in the S1 are enhanced in the chronic pain model, but the increased inhibition is insufficient to completely counterbalance the increased excitation and alleviate the symptoms of chronic pain.
A Competition-Based Mechanism Mediates Developmental Refinement of Tectal Neuron Receptive Fields
Authors: Dong Wei , Aizenman Carlos D.
Published: November 2012

Neural activity plays an important role in development and maturation of visual circuits in the brain. Activity can be instructive in refining visual projections by directly mediating formation and elimination of specific synaptic contacts through competition-based mechanisms. Alternatively, activity could be permissive—regulating production of factors that create a favorable environment for circuit refinement. Here we used theXenopus laevistadpole visual system to test whether activity is instructive or permissive for shaping development of the retinotectal circuit.In vivospike output was dampened in a small subgroup of tectal neurons, starting from developmental stages 44–46, by overexpressing Shaker-likeXenopusKv1.1 potassium channels using electroporation. Tadpoles were then reared until stage 49, a time period when significant refinement of the retinotectal map occurs. Kv1.1-expressing neurons had significantly decreased spike output in response to both current injection and visual stimuli compared to untransfected controls, with spiking occurring during a more limited time interval. We found that Kv1.1-expressing neurons had larger visual receptive fields, decreased receptive field sharpness, and more persistent recurrent excitation than control neurons, all of which are characteristics of immature neurons. Transfected cells, however, had normal spontaneous excitatory synaptic currents and dendritic arbors. These results suggest that spike output of a tectal neuron plays an important instructive role in development of its receptive field properties and refinement of local circuits. However, other activity-dependent processes, such as synaptogenesis and dendritic growth, remain unaffected due to the permissive environment created by otherwise normal network activity.
Detecting Representations of Recent and Remote Autobiographical Memories in vmPFC and Hippocampus
Authors: Bonnici Heidi M. , Chadwick Martin J. , Lutti Antoine , Hassabis Demis , Weiskopf Nikolaus , Maguire Eleanor A.
Published: November 2012

How autobiographical memories are represented in the human brain and whether this changes with time are questions central to memory neuroscience. Two regions in particular have been consistently implicated, the ventromedial prefrontal cortex (vmPFC) and the hippocampus, although their precise contributions are still contested. The key question in this debate, when reduced to its simplest form, concerns where information about specific autobiographical memories is located. Here, we availed ourselves of the opportunity afforded by multivoxel pattern analysis to provide an alternative to conventional neuropsychological and fMRI approaches, by detecting representations of individual autobiographical memories in patterns of fMRI activity. We examined whether information about specific recent (two weeks old) and remote (10 years old) autobiographical memories was represented in vmPFC and hippocampus, and other medial temporal and neocortical regions. vmPFC contained information about recent and remote autobiographical memories, although remote memories were more readily detected there, indicating that consolidation or a change of some kind had occurred. Information about both types of memory was also present in the hippocampus, suggesting it plays a role in the retrieval of vivid autobiographical memories regardless of remoteness. Interestingly, we also found that while recent and remote memories were both represented within anterior and posterior hippocampus, the latter nevertheless contained more information about remote memories. Thus, like vmPFC, the hippocampus too respected the distinction between recent and remote memories. Overall, these findings clarify and extend our view of vmPFC and hippocampus while also informing systems-level consolidation and providing clear targets for future studies.